CN113329736B - Self-emulsifying oral preparation of terpene medicinal composition, its preparation method and application - Google Patents
Self-emulsifying oral preparation of terpene medicinal composition, its preparation method and application Download PDFInfo
- Publication number
- CN113329736B CN113329736B CN201980087982.3A CN201980087982A CN113329736B CN 113329736 B CN113329736 B CN 113329736B CN 201980087982 A CN201980087982 A CN 201980087982A CN 113329736 B CN113329736 B CN 113329736B
- Authority
- CN
- China
- Prior art keywords
- self
- emulsifying
- limonene
- emulsifier
- pinene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 79
- 239000000203 mixture Substances 0.000 title claims description 83
- 150000003505 terpenes Chemical class 0.000 title abstract description 38
- 235000007586 terpenes Nutrition 0.000 title abstract description 38
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 claims abstract description 120
- GRWFGVWFFZKLTI-UHFFFAOYSA-N α-pinene Chemical compound CC1=CCC2C(C)(C)C1C2 GRWFGVWFFZKLTI-UHFFFAOYSA-N 0.000 claims abstract description 114
- 239000003814 drug Substances 0.000 claims abstract description 63
- 235000001510 limonene Nutrition 0.000 claims abstract description 60
- 229940087305 limonene Drugs 0.000 claims abstract description 60
- 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 57
- MVNCAPSFBDBCGF-UHFFFAOYSA-N alpha-pinene Natural products CC1=CCC23C1CC2C3(C)C MVNCAPSFBDBCGF-UHFFFAOYSA-N 0.000 claims abstract description 57
- 229960005233 cineole Drugs 0.000 claims abstract description 57
- WEEGYLXZBRQIMU-UHFFFAOYSA-N 1,8-cineole Natural products C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 claims abstract description 56
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 54
- 239000004519 grease Substances 0.000 claims abstract description 11
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 57
- WEEGYLXZBRQIMU-WAAGHKOSSA-N Eucalyptol Chemical compound C1C[C@H]2CC[C@]1(C)OC2(C)C WEEGYLXZBRQIMU-WAAGHKOSSA-N 0.000 claims description 54
- 239000003921 oil Substances 0.000 claims description 54
- 235000019198 oils Nutrition 0.000 claims description 54
- 238000009472 formulation Methods 0.000 claims description 37
- 238000002156 mixing Methods 0.000 claims description 33
- 239000003937 drug carrier Substances 0.000 claims description 31
- 238000003756 stirring Methods 0.000 claims description 31
- 239000007901 soft capsule Substances 0.000 claims description 30
- 239000007957 coemulsifier Substances 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 23
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 22
- 229920000053 polysorbate 80 Polymers 0.000 claims description 22
- 239000004480 active ingredient Substances 0.000 claims description 21
- 239000004359 castor oil Substances 0.000 claims description 21
- 235000019438 castor oil Nutrition 0.000 claims description 21
- 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 21
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 claims description 20
- -1 polyoxyethylene Polymers 0.000 claims description 20
- 229960004063 propylene glycol Drugs 0.000 claims description 20
- 239000003549 soybean oil Substances 0.000 claims description 20
- 235000012424 soybean oil Nutrition 0.000 claims description 20
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 19
- 239000002202 Polyethylene glycol Substances 0.000 claims description 18
- 229920001223 polyethylene glycol Polymers 0.000 claims description 18
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 claims description 17
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 16
- 125000005456 glyceride group Chemical group 0.000 claims description 15
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 13
- 239000002285 corn oil Substances 0.000 claims description 11
- 235000005687 corn oil Nutrition 0.000 claims description 11
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 10
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 10
- 229940093471 ethyl oleate Drugs 0.000 claims description 10
- 239000007902 hard capsule Substances 0.000 claims description 10
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 9
- 208000023504 respiratory system disease Diseases 0.000 claims description 8
- 206010006451 bronchitis Diseases 0.000 claims description 6
- 229920000136 polysorbate Polymers 0.000 claims description 6
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 claims description 5
- 206010061218 Inflammation Diseases 0.000 claims description 4
- 230000004054 inflammatory process Effects 0.000 claims description 4
- 229960003511 macrogol Drugs 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 206010001076 Acute sinusitis Diseases 0.000 claims description 3
- 206010006458 Bronchitis chronic Diseases 0.000 claims description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
- 206010009137 Chronic sinusitis Diseases 0.000 claims description 3
- 208000013606 Fungal Lung disease Diseases 0.000 claims description 3
- 206010035664 Pneumonia Diseases 0.000 claims description 3
- 201000010001 Silicosis Diseases 0.000 claims description 3
- 230000001154 acute effect Effects 0.000 claims description 3
- 201000009267 bronchiectasis Diseases 0.000 claims description 3
- 208000007451 chronic bronchitis Diseases 0.000 claims description 3
- 208000027157 chronic rhinosinusitis Diseases 0.000 claims description 3
- 239000004615 ingredient Substances 0.000 claims description 3
- 201000003453 lung abscess Diseases 0.000 claims description 3
- 208000008128 pulmonary tuberculosis Diseases 0.000 claims description 3
- 201000009890 sinusitis Diseases 0.000 claims description 3
- 239000010642 eucalyptus oil Substances 0.000 claims description 2
- 229940044949 eucalyptus oil Drugs 0.000 claims description 2
- 229940057917 medium chain triglycerides Drugs 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 239000007788 liquid Substances 0.000 abstract description 40
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 35
- 125000002006 1,8-cineol group Chemical group 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- 239000012071 phase Substances 0.000 description 40
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 28
- 239000002245 particle Substances 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 239000002775 capsule Substances 0.000 description 16
- 235000013772 propylene glycol Nutrition 0.000 description 14
- 229940079593 drug Drugs 0.000 description 13
- 239000000839 emulsion Substances 0.000 description 12
- 230000008901 benefit Effects 0.000 description 10
- 238000010587 phase diagram Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 108010010803 Gelatin Proteins 0.000 description 8
- 239000006185 dispersion Substances 0.000 description 8
- 239000008273 gelatin Substances 0.000 description 8
- 229920000159 gelatin Polymers 0.000 description 8
- 235000019322 gelatine Nutrition 0.000 description 8
- 235000011852 gelatine desserts Nutrition 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 238000012216 screening Methods 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 238000005303 weighing Methods 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 206010067484 Adverse reaction Diseases 0.000 description 5
- 230000006838 adverse reaction Effects 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 230000002496 gastric effect Effects 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 210000004051 gastric juice Anatomy 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 238000003825 pressing Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 244000166124 Eucalyptus globulus Species 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000004945 emulsification Methods 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 239000010779 crude oil Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000004530 micro-emulsion Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 241001672694 Citrus reticulata Species 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 235000004692 Eucalyptus globulus Nutrition 0.000 description 1
- 208000012895 Gastric disease Diseases 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 206010062717 Increased upper airway secretion Diseases 0.000 description 1
- 235000019501 Lemon oil Nutrition 0.000 description 1
- 241000219926 Myrtaceae Species 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 241000218641 Pinaceae Species 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 235000011609 Pinus massoniana Nutrition 0.000 description 1
- 241000018650 Pinus massoniana Species 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 241001093501 Rutaceae Species 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000004081 cilia Anatomy 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 210000002969 egg yolk Anatomy 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000030135 gastric motility Effects 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000010501 lemon oil Substances 0.000 description 1
- 239000002960 lipid emulsion Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000000420 mucociliary effect Effects 0.000 description 1
- 239000007908 nanoemulsion Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 239000008601 oleoresin Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 208000026435 phlegm Diseases 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001522 polyglycol ester Polymers 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 208000018556 stomach disease Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Images
Classifications
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- 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
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
-
- 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
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pulmonology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Dispersion Chemistry (AREA)
- Otolaryngology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
A terpene pharmaceutical composition self-emulsifying oral preparation, its preparation method and application, the said self-emulsifying oral preparation includes the pharmaceutical composition of eucalyptol, limonene and alpha-pinene of the specific proportion and emulsifier, optional grease and auxiliary emulsifier, cooperate with each other among every component, make the terpene pharmaceutical composition self-emulsifying liquid medicine nature made stable, homogeneous, have improved the quality stability of the terpene pharmaceutical composition self-emulsifying oral preparation, has guaranteed the therapeutic effect of the medicament, suitable for clinical large-area popularization and use.
Description
PRIORITY INFORMATION
This application requests priority and benefit of a patent application with patent application number 201910036486.7 filed on day 1, month 15 of 2019 with the chinese national intellectual property office and is incorporated herein by reference in its entirety.
Technical Field
The invention relates to the technical field of pharmaceutical preparations, and relates to a self-emulsifying oral preparation of a terpene pharmaceutical composition, a preparation method and application thereof.
Background
The pharmaceutical composition containing eucalyptol, limonene and alpha-pinene can be used for relieving cough, diminishing inflammation, eliminating phlegm and promoting the discharge of contrast medium for respiratory disease patients, and can be used as an aerosol inhalation for improving the functional damage of mucociliary clearance system caused by rhinitis and nasosinusitis, for example, the prior art discloses a pharmaceutical composition fat emulsion injection containing eucalyptol, limonene and alpha-pinene and a preparation method thereof, wherein the injection comprises 0.0128-0.032% of eucalyptol, 0.0084-0.0210% of limonene, 0.0028-0.0070% of alpha-pinene, 10-30% of soybean oil for injection, 1.0-1.5% of yolk lecithin for injection or 0.8-1.5% of soybean phospholipid for injection, 2.0-2.5% of glycerol for injection and 100mL of water for injection, the injection has various effects of diluting sputum, promoting accelerated movement and anti-inflammatory of trachea and bronchus cilia, does not contain sugar, is suitable for patients with stomach diseases and is not suitable for patients in clinical use, but is suitable for emergency treatment because of patients, is not convenient for emergency treatment, but is expensive in clinical use. Therefore, there is a need to develop an oral formulation of a pharmaceutical composition comprising eucalyptol, limonene and alpha-pinene.
Self-emulsifying drug delivery systems (SEDDS) are homogeneous, clear, homogeneous solutions composed of an oil solution and a surfactant, and sometimes including a cosolvent. The system spontaneously forms an oil-in-water emulsion in the aqueous phase of gastric juice after oral administration due to gastric motility and the presence of an emulsifier. Compared with emulsion, SEDDS belongs to a thermodynamic stable system, and has the advantages of simple process, stable property and convenient storage. In addition, the self-emulsifying preparation is convenient to administer, can be prepared into various administration forms such as capsules, tablets, pellets and the like, is accurate in dosage and convenient to take, is suitable for large-scale production, and has great development prospect and application value.
However, eucalyptol, limonene and alpha-pinene are three different substances with certain differences in properties, self-emulsifying liquid medicine of terpene pharmaceutical compositions containing eucalyptol, limonene, alpha-pinene and the like prepared by using a surfactant and/or a cosolvent in the prior art is unstable and easy to generate layering phenomenon, and a large amount of non-emulsified oil drops of the medicine exist on the surface when the self-emulsifying liquid medicine is dispersed in water, so that uniform liquid medicine is difficult to form, the quality of a self-emulsifying preparation of the pharmaceutical composition is unstable, and the large-area popularization and application of the self-emulsifying liquid medicine are greatly limited.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is to overcome the defect of unstable preparation quality of the oral preparation of the pharmaceutical composition containing eucalyptol, limonene and alpha-pinene prepared by the existing method, so as to provide the self-emulsifying oral preparation of the terpene pharmaceutical composition. Meanwhile, the invention also provides a preparation method and application of the self-emulsifying oral preparation of the terpene pharmaceutical composition.
In order to solve the technical problems, the invention provides a self-emulsifying oral preparation. According to an embodiment of the invention, the self-emulsifying oral formulation comprises: active ingredients including eucalyptol, limonene and alpha-pinene; and a pharmaceutical carrier. The self-emulsifying oral preparation provided by the embodiment of the invention has the advantages of high stability, narrow particle size distribution range, fast drug absorption, high oral bioavailability and small gastrointestinal adverse reaction.
According to an embodiment of the present invention, the self-emulsifying oral formulation may further comprise at least one of the following additional technical features:
according to an embodiment of the invention, the self-emulsifying oral formulation comprises: 40 to 65 parts by weight of the eucalyptol; 25 to 45 parts by weight of the limonene; and 5 to 20 parts by weight of the alpha-pinene.
According to the embodiment of the invention, the weight ratio of the active ingredient to the drug carrier is (1-15): 10.
According to the embodiment of the invention, the weight ratio of the active ingredient to the drug carrier is (1-6): 10.
According to the embodiment of the invention, the weight ratio of the active ingredient to the drug carrier is (1-5): 10.
According to the embodiment of the invention, the weight ratio of the active ingredient to the drug carrier is (5-6): 10. The inventor finds that the weight ratio of the active ingredient to the drug carrier is (5-6): 10, the stability of the self-emulsifying oral preparation is further improved, the dispersed particle size in water is further reduced, the drug absorption is better, and the gastrointestinal reaction is further reduced.
According to an embodiment of the invention, the weight ratio of the active ingredient to the pharmaceutical carrier is 5.4.
According to an embodiment of the invention, the drug carrier comprises: an emulsifier; optionally a grease; and optionally a co-emulsifier.
According to an embodiment of the present invention, the emulsifier comprises at least one selected from tween, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, phospholipid, caprylic capric polyglycol ester.
According to an embodiment of the invention, the phospholipids comprise soy phospholipids.
According to an embodiment of the present invention, the oil or fat includes at least one selected from the group consisting of soybean oil, medium chain triglyceride, ethyl oleate, corn oil, and olive oil.
According to an embodiment of the present invention, the co-emulsifier comprises at least one selected from the group consisting of ethanol, 1, 2-propanediol, glycerol, polyethylene glycol, diethylene glycol monoethyl ether.
According to an embodiment of the invention, the drug carrier comprises: 10 to 50 parts by weight of the oil; 40 to 80 parts by weight of the emulsifier; and 5-30 parts by weight of the coemulsifier.
According to an embodiment of the invention, the drug carrier comprises: 10 to 35 parts by weight of the oil; 50 to 70 of said emulsifier; and 10-25 parts by weight of the coemulsifier.
According to an embodiment of the invention, the drug carrier comprises: 25 to 35 parts by weight of said medium chain triglycerides; 50-65 parts by weight of the caprylic/capric polyethylene glycol glyceride; and 10-15 parts by weight of diethylene glycol monoethyl ether.
According to an embodiment of the invention, the pharmaceutical carrier comprises: 0 to 5 parts by weight of the oil; 0 to 5 parts by weight of the co-emulsifier; 90 to 100 parts by weight of the emulsifier. The inventor finds that the dosage of the hydrophilic co-emulsifier is greatly reduced in the dosage range of the components of the drug carrier, so that the layering phenomenon of the concentrated solution is greatly reduced, and meanwhile, the inventor also finds that the dispersion particle size of the concentrated solution in water is greatly reduced, so that the drug absorption is promoted, and the adverse reaction of the gastrointestinal tract is reduced; moreover, the dosage of the grease is greatly reduced, only the oily active ingredients provide oily ingredients of the preparation, the usage of an oil phase is reduced on the basis of ensuring the self-emulsifying effect, and the dosage of auxiliary materials is reduced, so that the preparation is beneficial to being pressed into a smaller preparation form.
According to an embodiment of the invention, the emulsifier consists of at least two emulsifiers.
According to the embodiment of the invention, the emulsifier consists of a first emulsifier and a second emulsifier, the mass fraction of the first emulsifier is 20-80%, and the mass fraction of the second emulsifier is 10-70% based on the total mass of the self-emulsifying oral preparation.
According to an embodiment of the invention, said drug carrier consists of said emulsifier.
According to an embodiment of the present invention, the self-emulsifying oral formulation is in the form of a hard capsule, a soft capsule or a tablet.
According to an embodiment of the invention, the self-emulsifying oral formulation comprises: 18.2g of eucalyptol, 16.4g of limonene, 1.8g of alpha-pinene, 181.8g of soybean oil, 145.4g of tween 80 and 36.4g of propylene glycol; or
73.3g eucalyptol, 33.3g limonene, 26.6g alpha-pinene, 26.7g medium chain triglyceride, 213.4g caprylic capric polyethylene glycol glyceride, 26.7g diethylene glycol monoethyl ether; or
14.6g eucalyptol, 16.4g limonene, 5.4g alpha-pinene, 90.9g medium chain triglyceride, 236.6g caprylic capric polyethylene glycol glyceride, 36.4g diethylene glycol monoethyl ether; or
86.6g of eucalyptol, 40.0g of limonene, 6.6g of alpha-pinene, 93.4g of medium chain triglyceride, 133.4g of caprylic/capric macrogol glyceride, 40g of diethylene glycol monoethyl ether; or
53.3g eucalyptol, 53.3g limonene, 26.6g alpha-pinene, 26.7g ethyl oleate, 160.1g polyoxyethylene castor oil, 80.0g diethylene glycol monoethyl ether; or
78.0g eucalyptol, 36.0g limonene, 6.0g alpha-pinene, 126g corn oil, 140g polyoxyethylene hydrogenated castor oil, 14.0g propylene glycol; or
42.7g of eucalyptol, 28.0g of limonene, 9.3g of alpha-pinene, 80g of soybean oil, 180g of Tween 80 and 60g of PEG-400; or
69.3g of eucalyptol, 45.5g of limonene, 15.2g of alpha-pinene, 40g of corn oil, 170g of polyoxyethylene castor oil and 60g of propylene glycol; or
70.0g of eucalyptol, 45.5g of limonene, 14.5g of alpha-pinene, 40g of soybean oil, 180g of polyoxyethylene hydrogenated castor oil and 50g of propylene glycol; or
70.0g of eucalyptol, 45.5g of limonene, 14.5g of alpha-pinene, 50g of ethyl oleate, 160g of caprylic/capric polyethylene glycol glyceride and 60g of diethylene glycol monoethyl ether; or
69.3g of eucalyptol, 45.5g of limonene, 15.2g of alpha-pinene, 40g of soybean oil, 170g of Tween 80 and 60g of propylene glycol; or
69.3g of eucalyptol, 45.5g of limonene, 15.2g of alpha-pinene, 40g of soybean oil, 170g of Tween 80 and 60g of propylene glycol; or
75g of eucalyptol, 50g of limonene, 16g of alpha-pinene, 79g of Tween 80, and 180g of caprylic/capric macrogol; or
75g of eucalyptol, 50g of limonene, 16g of alpha-pinene, 165g of caprylic/capric polyethylene glycol glyceride and 94g of polyoxyethylene castor oil.
In a second aspect of the invention, the invention provides a process for the preparation of the self-emulsifying oral formulation as hereinbefore described. According to an embodiment of the invention, the method comprises: mixing said active ingredient with said pharmaceutical carrier so as to obtain said self-emulsifying oral formulation.
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 invention, further comprising encapsulating the mixture comprising the active ingredient and the pharmaceutical carrier in order to obtain a formulation.
According to an embodiment of the invention, the formulation is a soft capsule, a hard capsule or a tablet.
According to an embodiment of the present invention, mixing the active ingredient with the pharmaceutical carrier further comprises: subjecting the active ingredient and optionally the fat to a first mixing treatment so as to obtain an oil phase mixture; and carrying out second mixing treatment on the oil-phase mixture, the emulsifier and the optional coemulsifier.
According to an embodiment of the present invention, the first mixing process and the second mixing process are each independently performed under the following conditions: the temperature is 15-30 ℃; the stirring speed is as follows: 30-50 rpm; and/or the mixing time is 1 to 2 hours.
According to an embodiment of the invention, the medicament is for the treatment or prevention of a respiratory disease.
According to an embodiment of the invention, the respiratory disease comprises: at least one of acute sinusitis, chronic sinusitis, sinusitis operation inflammation, acute and chronic bronchitis, pneumonia, bronchiectasis, pulmonary abscess, chronic obstructive pulmonary disease, pulmonary fungal infection, pulmonary tuberculosis, and silicosis.
In a third aspect of the invention, a method of treating or preventing a respiratory disorder is presented. According to an embodiment of the invention, the method comprises administering the self-emulsifying oral formulation as described above to a patient with a respiratory disorder. According to the method provided by the embodiment of the invention, the self-emulsifying oral preparation has the advantages of faster absorption, higher oral bioavailability, weaker gastrointestinal reaction of patients and better treatment 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 invention, the respiratory disease comprises: at least one of acute sinusitis, chronic sinusitis, sinusitis operation inflammation, acute and chronic bronchitis, pneumonia, bronchiectasis, pulmonary abscess, chronic obstructive pulmonary disease, pulmonary fungal infection, pulmonary tuberculosis, and silicosis.
The technical scheme of the invention has the following advantages:
1. the terpene medicinal composition self-emulsifying oral preparation provided by the invention comprises a medicinal composition of eucalyptol, limonene and alpha-pinene in a specific proportion, grease, an emulsifier and an auxiliary emulsifier, and all the components are matched with each other, so that the prepared terpene medicinal composition self-emulsifying liquid medicine is stable and uniform in property, the quality stability of the terpene medicinal composition self-emulsifying oral preparation is improved, the treatment effect of the medicine is ensured, and the terpene medicinal composition self-emulsifying oral preparation is suitable for large-area clinical popularization and use.
2. The terpene medicinal composition self-emulsifying oral preparation provided by the invention further limits the types and contents of the emulsifying agent and the co-emulsifying agent, improves the uniformity of the self-emulsifying liquid medicine of the terpene medicinal composition, and is beneficial to improving the quality of the self-emulsifying oral preparation.
3. The terpene pharmaceutical composition self-emulsifying oral preparation provided by the invention can spontaneously form an oil-in-water microemulsion in a water phase of gastric juice after oral administration under the action of gastric peristalsis and an emulsifier and an auxiliary emulsifier, effectively cover the taste of eucalyptol, limonene and alpha-pinene, reduce the stimulation of the medicine to the gastrointestinal tract, avoid the occurrence of adverse reactions such as nausea, vomiting, diarrhea and the like, and is suitable for patients with a gastric disease history.
4. The terpene medicine composition self-emulsifying oral preparation provided by the invention enters gastric juice through oral administration, and contacts with water in the gastric juice to form medicine-carrying microemulsion, the medicine composition exists in the tiny oil drops and is rapidly distributed in the whole stomach, the dissolution of the water-insoluble medicine is greatly improved by depending on the huge specific surface area of the tiny oil drops, so that the medicine can more easily pass through a hydration layer of the gastrointestinal wall, the permeability of epithelial cells of the medicine is increased, the absorption of the medicine is promoted, and the problem that the terpene medicine is difficult to absorb in a human body is effectively solved.
5. The terpene pharmaceutical composition self-emulsifying oral preparation provided by the invention comprises eucalyptol, limonene and alpha-pinene which are all natural products, and has the advantages of wide sources, simple process, low cost, definite chemical structure and composition, low toxicity and high safety.
6. The preparation method of the self-emulsifying oral preparation of the terpene pharmaceutical composition provided by the invention has the advantages of simple process, low cost, good stability and controllable quality, can be used for preparing self-emulsifying liquid medicine into oral dosage forms such as soft capsules, hard capsules, tablets, granules, dropping pills or pellets and the like, and is suitable for large-scale batch production.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:
FIG. 1 is a pseudo-ternary phase diagram of the mixed oil phase Tween 80-PEG-400 according to the embodiment of the present invention;
FIG. 2 is a pseudo-ternary phase diagram of mixed oil phase Tween 80-Transcutol according to the embodiment of the invention;
FIG. 3 is a pseudo-ternary phase diagram of a mixed oil phase-Labrasol-PEG 400 according to an embodiment of the present invention;
FIG. 4 is a pseudo-ternary phase diagram of the mixed oil phase Labrasol Transcutol according to an embodiment of the present invention;
FIG. 5 is a pseudo-ternary phase diagram of the oil-free co-emulsifier-eucalyptus oil-emulsifier 1-emulsifier 2 according to an embodiment of the present invention;
fig. 6 is a representative particle size distribution diagram of a self-emulsifying drug solution in accordance with an embodiment of the present invention.
Detailed Description
Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like reference numerals refer to the same or similar elements or elements having the same or similar functions throughout. The embodiments described below with reference to the accompanying drawings are illustrative only for the purpose of explaining the present invention, and are not to be construed as limiting the present invention.
It should be noted that the terms "first" and "second" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or to implicitly indicate the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Further, in the description of the present invention, "a plurality" means two or more unless otherwise specified.
The invention mainly researches the prescription composition and the preparation process of the self-emulsifying preparation from three parts of preliminary prescription screening, drawing of a pseudo-ternary phase diagram and an orthogonal test to determine the optimal prescription of the self-emulsifying concentrated solution of the pharmaceutical composition.
(1) Preliminary screening of prescriptions
Fixing the formula proportion of the self-emulsifying concentrated solution to be unchanged, respectively preparing the self-emulsifying concentrated solution by using different grease, emulsifiers and co-emulsifiers, and screening the proper grease, emulsifiers and co-emulsifiers according to the self-emulsifying effect.
The formulation for designing the self-emulsifying formulation was:
wherein the screened oil comprises soybean oil, corn oil, medium chain triglyceride, and ethyl oleate; the screened emulsifying agent comprises Tween 80, polyoxyethylene castor oil (EL-35), polyoxyethylene hydrogenated castor oil (RH-40), caprylic capric polyethylene glycol glyceride (Labrasol); the screened co-emulsifier includes propylene glycol, glycerol, diethylene glycol monoethyl ether (Transcutol), and PEG-400.
The fixed oil was soybean oil, and the results of screening the types of emulsifiers and co-emulsifiers are shown in table 1.
TABLE 1 preliminary screening results for emulsifiers, coemulsifiers
The fixed emulsifier is tween 80, the co-emulsifier is propylene glycol, and the results of screening the grease types are shown in table 2.
TABLE 2 results of screening oil and fat species
By combining the test results, the common soybean oil is selected as the grease, the Tween 80 and the caprylic/capric polyethylene glycol glyceride with good self-emulsifying effect are used as the emulsifying agents, and the PEG-400 and the diethylene glycol monoethyl ether are used as the auxiliary emulsifying agents for subsequent tests.
In addition, the inventor unexpectedly discovers in experiments that if the dosage of the grease and the co-emulsifier is reduced as much as possible, and the composite emulsifier is adopted, the emulsification rate is greatly improved, and the particle size of emulsion drops is greatly reduced.
Table 3 shows the appearance of the concentrate, the emulsification rate and the emulsion droplet size data after the inventors tried to reduce the amount of grease or co-emulsifier during the experiment.
Table 3:
(2) Drawing of pseudo ternary phase diagram
And drawing a pseudo ternary phase diagram of each combined oil phase-emulsifier-co-emulsifier, and determining an effective self-emulsifying area formed by each prescription. The results are shown in FIGS. 1-4 (marked with effective self-emulsifying region), and the mass ratio of the effective self-emulsifying region formed by taking the pseudo-ternary phase diagram of oil phase-Tween 80-PEG-400 (FIG. 1) is oil phase 0.1-0.4, tween 80 0.4-0.9, and PEG-400 0.1-0.6. And selecting a prescription proportion with higher oil phase content for subsequent tests.
In addition, the inventor draws a pseudo ternary phase diagram by using a grease-free auxiliary emulsifier-eucalyptol and pinene oil-emulsifier 1-emulsifier 2, and determines effective self-emulsifying areas formed by each formula, and the result is shown in figure 5. As can be seen from the figure, in the range of the effective self-emulsifying region, the proportion of the eucalyptus and limonene oil is 10-60%, the proportion of the auxiliary material emulsifier 1 is 20-80%, and the proportion of the emulsifier 2 is 10-70%. The ratio of drug to carrier is thus 1: 10 portions of carriers (1.1-15).
(3) Quadrature test
And designing a proper factor level table and an orthogonal test table, and screening an optimal formula of the self-emulsifying concentrated solution through the self-emulsifying rate and the emulsion drop particle size.
The factor levels for designing the orthogonal test are shown in table 4, using the pharmaceutical composition and soybean oil as oil phase, tween 80 as emulsifier, and PEG-400 as co-emulsifier.
TABLE 4 orthogonal test factor horizon
The test results are shown in Table 5.
TABLE 5 results of orthogonal tests
By visual analysis, the optimal formula is 0.30g of oil phase, 0.50g of Tween 80 and 0.15g of PEG-400. The formula is repeated three times, the dispersion rate of the prepared self-emulsifying concentrated solution in water is 20-40 s, and the particle size of emulsion drops is 150-180 nm.
The following examples are provided to better understand the present invention, not to limit the best mode, and not to limit the content and protection scope of the present invention, and any product that is the same or similar to the present invention and is obtained by combining the present invention with other features of the prior art and the present invention falls within the protection scope of the present invention.
The examples do not show the specific experimental steps or conditions, and can be performed according to the conventional experimental steps described in the literature in the field. The reagents or instruments used are not indicated by manufacturers, and are all conventional reagent products which can be obtained commercially.
In the following examples, eucalyptol, limonene and alpha-pinene may be prepared as follows: the eucalyptol is obtained by rectifying eucalyptus oil (crude oil) prepared from eucalyptus globulus labill of eucalyptus of Myrtaceae, the content of which is 80-85%; squeezing lemon peel of Citrus reticulata Blanco of Citrus of Rutaceae, distilling with steam to obtain lemon oil (crude oil), and rectifying to obtain limonene with content of 93% or more; steam distilling and refining oleoresin exuded from Pinus massoniana of Pinaceae to obtain alpha-pinene with content of more than 90%.
EXAMPLE 1 preparation of terpene pharmaceutical compositions self-emulsifying Soft capsules
The prescription of the self-emulsifying liquid medicine is as follows:
the preparation method comprises the following steps:
(1) Taking eucalyptol, limonene, alpha-pinene and soybean oil in the formula amount, stirring at the rotation speed of 50rpm for 1 hour at 15 ℃, and uniformly mixing to obtain an oil phase;
(2) Adding the Tween 80 and the propylene glycol of the prescription amount into the oil phase, stirring at the rotation speed of 50rpm for 1 hour at 15 ℃, and uniformly mixing to form a uniform self-emulsifying liquid medicine;
(3) According to the weight ratio of 1:0.5:1.1 preparing capsule skin by weighing gelatin, glycerol and water;
(4) And (3) pressing the self-emulsifying liquid medicine obtained in the step (2) and the capsule skin obtained in the step (3) on a soft capsule machine in a conventional mode, and setting in a setting machine to prepare the terpene medicinal composition self-emulsifying soft capsule.
EXAMPLE 2 preparation of terpene-based pharmaceutical composition self-emulsifying Soft Capsule
The prescription of the self-emulsifying liquid medicine is as follows:
the preparation method comprises the following steps:
(1) Taking eucalyptol, limonene, alpha-pinene and medium-chain triglyceride in the formula amount, stirring for 2 hours at the rotation speed of 30rpm at the temperature of 30 ℃, and uniformly mixing to obtain an oil phase;
(2) Adding Labrasol and Transcutol in the prescription amount into the oil phase, stirring at 30 ℃ and 30rpm for 2 hours, and uniformly mixing to form a uniform self-emulsifying liquid medicine;
(3) Weighing gelatin, glycerol and water according to the weight ratio of 1;
(4) And (3) pressing the self-emulsifying liquid medicine obtained in the step (2) and the capsule skin obtained in the step (3) on a soft capsule machine in a conventional mode, and setting in a setting machine to prepare the terpene medicinal composition self-emulsifying soft capsule.
EXAMPLE 3 preparation of terpene pharmaceutical compositions self-emulsifying Soft capsules
The prescription of the self-emulsifying liquid medicine is as follows:
the preparation method is the same as example 2.
EXAMPLE 4 preparation of terpene-based pharmaceutical composition self-emulsifying Soft Capsule
The prescription of the self-emulsifying liquid medicine is as follows:
the preparation method is the same as example 2.
EXAMPLE 5 preparation of terpene pharmaceutical compositions self-emulsifying hard capsules
The prescription of the self-emulsifying liquid medicine is as follows:
the preparation method comprises the following steps:
(1) Taking eucalyptol, limonene, alpha-pinene and ethyl oleate in the formula amount, stirring for 2 hours at 20 ℃, and uniformly mixing to obtain an oil phase;
(2) Adding the polyoxyethylene castor oil and the diethylene glycol monoethyl ether in the formula amount into the oil phase, and stirring for 2 hours at 20 ℃ to uniformly mix to form a uniform self-emulsifying liquid medicine;
(3) And (3) dripping the self-emulsifying liquid medicine obtained in the step (2) into micropowder silica gel under the condition of stirring, adding magnesium stearate, and subpackaging into hard capsules to obtain the terpene medicinal composition self-emulsifying hard capsules.
EXAMPLE 6 preparation of terpene-based pharmaceutical composition self-emulsifying tablet
The prescription of the self-emulsifying liquid medicine is as follows:
the preparation method comprises the following steps:
(1) Taking eucalyptol, limonene, alpha-pinene and corn oil in the formula amount, and stirring for 2 hours at 20 ℃ to be uniformly mixed to obtain an oil phase;
(2) Adding the polyoxyethylene hydrogenated castor oil and propylene glycol of the formula amount into an oil phase, and stirring for 2 hours at 20 ℃ to uniformly mix to form a uniform self-emulsifying liquid medicine;
(3) Dripping the self-emulsifying liquid medicine obtained in the step (2) into superfine silica gel powder under the stirring condition, adding auxiliary materials such as microcrystalline cellulose, spray-dried lactose, magnesium stearate and the like, and preparing the terpene medicinal composition self-emulsifying tablet by adopting a conventional direct tabletting method.
EXAMPLE 7 preparation of terpene pharmaceutical compositions self-emulsifying Soft capsules
The prescription of the self-emulsifying liquid medicine is as follows:
the preparation process comprises the following steps:
(1) Taking eucalyptol, limonene, alpha-pinene and soybean oil in the prescription amount, stirring for 1 hour at 20 ℃, and uniformly mixing to obtain an oil phase;
(2) Adding tween 80 and PEG-400 into the oil phase, and stirring for 2 hr at 20 deg.C to obtain self-emulsifying concentrated solution;
(3) Preparing capsule skin by weighing gelatin, glycerol and water according to the weight ratio of 1;
(4) And (3) preparing the self-emulsifying concentrated solution obtained in the step (2) and the capsule shell obtained in the step (3) into soft capsules in a conventional manner.
EXAMPLE 8 preparation of terpene-based pharmaceutical composition self-emulsifying Soft Capsule
The prescription of the self-emulsifying liquid medicine is as follows:
the preparation process comprises the following steps:
(1) Taking eucalyptol, limonene, alpha-pinene and corn oil in the prescription amount, stirring for 2 hours at 20 ℃, and uniformly mixing to obtain an oil phase;
(2) Adding the polyoxyethylene castor oil and the propylene glycol into the oil phase according to the prescription amount, and stirring for 2 hours at 20 ℃ to uniformly mix to form self-emulsifying concentrated solution;
(3) Preparing capsule skin by weighing gelatin, glycerol and water according to the weight ratio of 1.4-0.6;
(4) And (3) preparing the self-emulsifying concentrated solution obtained in the step (2) and the capsule shell obtained in the step (3) into soft capsules in a conventional manner.
EXAMPLE 9 preparation of pharmaceutical composition self-emulsifying Soft Capsule
The prescription of the contents:
the preparation process is the same as example 6.
EXAMPLE 10 preparation of self-emulsifying Soft capsules of pharmaceutical composition
Content prescription:
the preparation process is the same as example 6.
EXAMPLE 11 preparation of pharmaceutical composition self-emulsifying hard capsules
Content prescription:
the preparation process comprises the following steps:
(1) Taking eucalyptol, limonene, alpha-pinene and soybean oil in the formula amount, and stirring for 2 hours at 20 ℃ to be uniformly mixed to obtain an oil phase;
(2) Adding the Tween 80 and the propylene glycol into the oil phase according to the prescription amount, and stirring for 2 hours at 20 ℃ to uniformly mix to form a self-emulsifying concentrated solution;
(3) And (3) dripping the self-emulsifying concentrated solution obtained in the step (2) into a proper amount of superfine silica gel powder under stirring, adding magnesium stearate, and subpackaging into hard capsules.
EXAMPLE 12 preparation of pharmaceutical composition self-emulsifying tablet
The prescription of the concentrated solution is as follows:
the preparation process comprises the following steps:
(1) Taking eucalyptol, limonene, alpha-pinene and soybean oil in the prescription amount, stirring for 2 hours at 20 ℃, and uniformly mixing to obtain an oil phase;
(2) Adding the Tween 80 and the propylene glycol into the oil phase according to the prescription amount, and stirring for 2 hours at 20 ℃ to uniformly mix to form a self-emulsifying concentrated solution;
(3) And (3) dripping the self-emulsifying concentrated solution obtained in the step (2) into a proper amount of superfine silica gel powder under stirring, adding auxiliary materials such as microcrystalline cellulose, spray-dried lactose, magnesium stearate and the like, and preparing the self-emulsifying concentrated solution from the emulsifying tablets by a conventional direct tabletting method.
Example 13: preparation of self-emulsifying soft capsule of medicinal composition
Content prescription:
the preparation process comprises the following steps:
(1) Taking eucalyptol, limonene and alpha-pinene in the prescription amount, stirring for 1 hour at 20 ℃, and uniformly mixing to obtain an oil phase;
(2) Adding Tween 80 and polyethylene glycol caprylic capric acid into the oil phase, stirring at 20 deg.C for 2 hr, and mixing to obtain self-emulsifying concentrated solution;
(3) Preparing capsule skin by weighing gelatin, glycerol and water according to the weight ratio of 1;
(4) And (3) preparing the self-emulsifying concentrated solution obtained in the step (2) and the capsule shell obtained in the step (3) into soft capsules in a conventional manner.
EXAMPLE 14 preparation of self-emulsifying Soft Capsule for pharmaceutical composition
The prescription of the contents:
the preparation process comprises the following steps:
(1) Taking eucalyptol, limonene and alpha-pinene in the prescription amount, stirring for 1 hour at 20 ℃, and uniformly mixing to obtain an oil phase;
(2) Adding prescription dose of caprylic/capric polyethylene glycol glyceride and polyoxyethylene castor oil into an oil phase, stirring for 2 hours at 20 ℃, and uniformly mixing to form a self-emulsifying concentrated solution;
(3) Preparing capsule skin by weighing gelatin, glycerol and water according to the weight ratio of 1;
(4) And (3) preparing the self-emulsifying concentrated solution obtained in the step (2) and the capsule shell obtained in the step (3) into soft capsules in a conventional manner.
The inventors have found that the removal of hydrophilic co-emulsifiers from the self-emulsifying concentrates of examples 13 and 14 reduces the stratification of the concentrates, facilitates the mixing of large amounts of drug, and improves the uniformity of drug content.
Comparative example 1 preparation of terpene-based pharmaceutical composition self-emulsifying Soft Capsule Using existing self-emulsifying formulation Process
According to the disclosed self-emulsifying preparation formula, the formula of the self-emulsifying medicinal liquid of the terpene medicinal composition is designed as follows:
the preparation method is disclosed as follows:
(1) Taking eucalyptol, limonene and alpha-pinene in the prescription amount, adding ethyl oleate, and mixing uniformly to obtain an oil phase;
(2) Mixing the Tween 80 and PEG-400 according to the prescription amount, and uniformly mixing by using a magnetic stirrer to obtain an emulsified phase;
(3) Mixing the oil phase and the emulsified phase, and uniformly mixing in a stirring, vibrating, ultrasonic or vortex mode to form self-emulsifying liquid medicine;
(4) According to the weight ratio of 1:0.45:1.1 preparing capsule skin by weighing gelatin, glycerol and water;
(5) And (4) pressing the self-emulsifying liquid medicine obtained in the step (3) and the capsule skin obtained in the step (4) on a soft capsule machine in a conventional mode, and setting in a setting machine to prepare the self-emulsifying soft capsule.
Comparative example 2 preparation of terpene-based pharmaceutical composition self-emulsifying Soft Capsule Using the existing formulation of self-emulsifying preparation and the preparation method of the present invention
According to the disclosed self-emulsifying preparation formula, the formula of the self-emulsifying medicinal liquid of the terpene medicinal composition is designed as follows:
the preparation method comprises the following steps:
(1) Taking eucalyptol, limonene, alpha-pinene and ethyl oleate in the formula amount, stirring at the rotating speed of 50rpm for 1 hour at 15 ℃, and uniformly mixing to obtain an oil phase;
(2) Adding Tween 80 and PEG-400 into the oil phase, stirring at 15 deg.C and 50rpm for 1 hr to obtain emulsified medicinal liquid;
(3) According to the weight ratio of 1:0.5:1.1 preparing capsule skin by weighing gelatin, glycerol and water;
(4) And (3) pressing the self-emulsifying liquid medicine obtained in the step (2) and the capsule skin obtained in the step (3) on a soft capsule machine in a conventional mode, and setting in a setting machine to prepare the self-emulsifying soft capsule.
EXAMPLE 15 Property Observation of different self-emulsifying formulations
The oil phase, the emulsifier and the co-emulsifier are respectively used as one phase, the components are fully mixed according to different proportions, the mixture is kept stand for 2 hours, and whether a uniform, transparent and non-layered solution is formed or not is observed visually. A formulation which formed a uniform, transparent solution was taken out by 0.5mL, added dropwise to 50mL of purified water at 37 ℃ with stirring at 50rpm, and observed whether a clear and transparent emulsion was formed.
The results show that: 1. the self-emulsifying liquid medicines in the comparative examples 1 and 2 are layered after standing, the self-emulsifying liquid medicine layering phenomenon of the comparative example 1 is more serious, and the self-emulsifying liquid medicines of the examples 1 to 11 of the invention are not layered after standing; 2. the self-emulsifying liquid medicines of comparative examples 1 and 2 cannot be rapidly dispersed into uniform emulsions in water, and a large number of oil droplets float on the surface of water after dispersion, and effective self-emulsification cannot be realized, whereas the self-emulsifying liquid medicines of examples 1 to 11 of the present invention can be rapidly and uniformly dispersed in water, and the formed emulsion droplets have small particle sizes and uniform particle size distribution.
It is thus understood that the self-emulsifying preparation techniques disclosed in the prior art are not easily applied directly to the terpene-based pharmaceutical composition of the present invention, and that the self-emulsifying preparations of terpene-based pharmaceutical compositions prepared according to the prior art cannot achieve a good self-emulsifying effect.
Example 16 particle size measurement of self-emulsifying Dispersion
0.5mL of the self-emulsified liquid medicines of examples 1 to 11 was dispersed in 50mL of purified water at 37 ℃, and the particle size of the emulsion droplets was measured by a laser particle sizer for 2mL of the dispersion, and the results are shown in Table 6, and a typical particle size distribution chart of the self-emulsified liquid medicine in example 1 is shown in FIG. 6. The self-emulsified concentrated solution prepared by the formulation of example 1 can be rapidly dispersed in water into a nano-sized emulsion with uniform particle size, the dispersion rate is 20-40 s, the average particle size is (161.4 + -17.6) nm, and the polydispersity index is 0.278 + -0.101.
Table 6: examples 1 to 14 self-emulsifying agent Dispersion Rate and emulsion droplet particle diameter
As can be seen from Table 6 and FIG. 6, the self-emulsifying drug solutions of examples 1 to 14 of the present invention were rapidly dispersed in water into nano-sized emulsions having uniform particle diameters, a dispersion rate of 10 to 65 seconds, an average particle diameter of 40 to 190nm, and a polydispersity of 0.150 to 0.32. The self-emulsifying liquid medicine of the examples 13 and 14 has the advantages that the dispersed particle size in water is obviously reduced, the average particle size of the examples 1 to 12 is 140 to 190nm, the particle size of the example 13 is only 100 to 110nm, the particle size of the example 14 is 40 to 50nm, the examples 13 and 14 have obviously smaller particle sizes, the medicine absorption is promoted, the adverse reaction of gastrointestinal tracts is reduced, no oil phase is used, the using amount of auxiliary materials is effectively reduced, the cost is saved, and the self-emulsifying liquid medicine can be pressed into smaller soft capsules to be convenient to swallow.
The self-emulsifying liquid medicine prepared by the invention can rapidly disperse the eucalyptol, limonene and alpha-pinene medicinal composition into the nano-emulsion, has smaller particle size, is favorable for accelerating medicament absorption and simultaneously reduces adverse reaction of gastrointestinal tracts.
Although specific embodiments of the invention have been described in detail, those skilled in the art will appreciate. Various modifications and substitutions of those details may be made in light of the overall teachings of the disclosure, and such changes are intended to be within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an illustrative embodiment," "an example," "a specific example," or "some examples" or the like 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 do not necessarily 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.
Claims (20)
1. A self-emulsifying oral formulation comprising:
active ingredients including eucalyptol, limonene and alpha-pinene; and
a carrier of a medicine, wherein the medicine is prepared from a traditional Chinese medicine,
A. the drug carrier includes:
an emulsifier;
grease; and
an auxiliary emulsifying agent is added into the mixture,
the emulsifier comprises at least one selected from tween, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil and caprylic capric polyethylene glycol glyceride;
the oil comprises at least one selected from soybean oil, medium chain triglyceride, ethyl oleate and corn oil;
the coemulsifier comprises at least one selected from 1, 2-propylene glycol, polyethylene glycol and diethylene glycol monoethyl ether,
or,
B. the drug carrier is composed of a first emulsifier and a second emulsifier, the first emulsifier is caprylic/capric polyethylene glycol glyceride, and the second emulsifier is tween or polyoxyethylene castor oil.
2. The self-emulsifying oral formulation of claim 1, wherein the self-emulsifying oral formulation comprises:
40 to 65 parts by weight of the eucalyptol;
25 to 45 parts by weight of the limonene; and
5 to 20 parts by weight of the alpha-pinene.
3. The self-emulsifying oral formulation according to claim 2, wherein the weight ratio of the active ingredient to the pharmaceutical carrier is (1-15): 10.
4. The self-emulsifying oral formulation according to claim 2, wherein the weight ratio of the active ingredient to the pharmaceutical carrier is (1-5): 10.
5. The self-emulsifying oral formulation according to claim 2, wherein the weight ratio of the active ingredient to the pharmaceutical carrier is (5-6): 10.
6. The self-emulsifying oral formulation of claim 2, wherein the weight ratio of the active ingredient to the pharmaceutical carrier is 5.4.
7. The self-emulsifying oral formulation of claim 1, wherein the pharmaceutical carrier comprises:
10 to 50 parts by weight of the oil;
40 to 80 parts by weight of the emulsifier; and
5-30 parts by weight of the co-emulsifier.
8. The self-emulsifying oral formulation of claim 1, wherein the pharmaceutical carrier comprises:
10 to 35 parts by weight of the oil;
50 to 70 of the emulsifier; and
10-25 parts by weight of the co-emulsifier.
9. The self-emulsifying oral formulation of claim 1, wherein the pharmaceutical carrier comprises:
25 to 35 parts by weight of said medium chain triglycerides;
50-65 parts by weight of the caprylic/capric polyethylene glycol glyceride; and
10 to 15 parts by weight of diethylene glycol monoethyl ether.
10. The self-emulsifying oral formulation of claim 1, wherein the pharmaceutical carrier comprises:
0 to 5 parts by weight of the oil;
0 to 5 parts by weight of the co-emulsifier;
90 to 100 parts by weight of the emulsifier.
11. The self-emulsifying oral preparation according to claim 1, wherein the first emulsifier is present in an amount of 20 to 80% by mass and the second emulsifier is present in an amount of 10 to 70% by mass, based on the total mass of the self-emulsifying oral preparation.
12. The self-emulsifying oral formulation according to any one of the preceding claims, wherein the self-emulsifying oral formulation is in the form of a hard capsule, a soft capsule or a tablet.
13. The self-emulsifying oral formulation according to any one of claims 1 to 11, comprising:
18.2g of eucalyptol, 18.2g,
16.4g of limonene, 16.4g,
1.8g of alpha-pinene,
181.8g of soybean oil,
145.4g of Tween 80, and the like,
36.4g of propylene glycol; or
73.3g of eucalyptol, and the like,
33.3g of limonene, 33.3g,
26.6g of alpha-pinene,
26.7g of a medium chain triglyceride,
213.4g of caprylic/capric macrogol glyceride,
26.7g diethylene glycol monoethyl ether; or
14.6g of eucalyptol, namely,
16.4g of limonene, 16.4g,
5.4g of alpha-pinene,
90.9g of a medium chain triglyceride,
236.6g of caprylic capric acid polyethylene glycol glyceride,
36.4g diethylene glycol monoethyl ether; or
86.6g of eucalyptol, the rest of the ingredients are added,
40.0g of limonene was added to the mixture,
6.6g of alpha-pinene,
93.4g of a medium chain triglyceride,
133.4g of caprylic/capric macrogol glyceride,
40g of diethylene glycol monoethyl ether; or
53.3g of eucalyptol, namely,
53.3g of limonene was added as a mixture,
26.6g of alpha-pinene,
26.7g of ethyl oleate are added to the solution,
160.1g of a polyoxyethylated castor oil,
80.0g of diethylene glycol monoethyl ether; or
78.0g of eucalyptol, a coarse powder,
36.0g of limonene was added to the mixture,
6.0g of alpha-pinene,
126g of corn oil, namely, corn oil,
140g of a polyoxyethylene hydrogenated castor oil,
14.0g propylene glycol; or
42.7g of eucalyptol, namely,
28.0g of limonene was added as a mixture,
9.3g of alpha-pinene,
80g of soybean oil (80 g),
180g of Tween-80 (in g),
60g of PEG-400; or
69.3g of eucalyptol, namely,
45.5g of limonene was added to the mixture,
15.2g of alpha-pinene,
40g of corn oil, namely corn oil,
170g of a polyoxyethylene castor oil,
60g of propylene glycol; or
70.0g of eucalyptol, and the like,
45.5g of limonene was added as a mixture,
14.5g of alpha-pinene,
40g of soybean oil (40 g),
180g of polyoxyethylene hydrogenated castor oil,
50g of propylene glycol; or
70.0g of eucalyptol is added,
45.5g of limonene was added to the mixture,
14.5g of alpha-pinene,
50g of ethyl oleate are added to the mixture,
160g of caprylic capric acid polyethylene glycol glyceride,
60g of diethylene glycol monoethyl ether; or
69.3g of eucalyptol, namely,
45.5g of limonene was added to the mixture,
15.2g of alpha-pinene,
40g of a soybean oil (40 g),
170g of Tween 80, and a pharmaceutically acceptable carrier,
60g of propylene glycol; or
75g of eucalyptol and a mixture of the following ingredients,
50g of a mixture of limonene and limonene,
16g of alpha-pinene, which is,
79g of Tween 80, and a stirring device,
180g caprylic capric acid polyethylene glycol glyceride; or
75g of the eucalyptus oil is added,
50g of a mixture of limonene and limonene,
16g of alpha-pinene, which is,
165g of caprylic capric acid polyethylene glycol glyceride,
94g of polyoxyethylated castor oil.
14. A process for preparing the self-emulsifying oral formulation of any preceding claim, comprising: mixing said active ingredient with said pharmaceutical carrier so as to obtain said self-emulsifying oral formulation.
15. The method of claim 14, further comprising encapsulating a mixture comprising the active ingredient and the pharmaceutical carrier to obtain a formulation.
16. The method of claim 15, wherein the formulation is a soft capsule, a hard capsule, or a tablet.
17. The method of claim 14, wherein mixing the active ingredient with the pharmaceutical carrier further comprises:
subjecting the active ingredient and optionally the fat to a first mixing treatment so as to obtain an oily phase mixture;
and carrying out second mixing treatment on the oil-phase mixture, the emulsifier and the optional coemulsifier.
18. The method according to claim 17, wherein the first mixing process and the second mixing process are each independently performed under the following conditions:
the temperature is 15-30 ℃;
the stirring speed is as follows: 30-50 rpm; and/or
The mixing time is 1 to 2 hours.
19. Use of a self-emulsifying oral formulation according to any one of claims 1 to 13 in the manufacture of a medicament for the treatment or prevention of a respiratory disease.
20. The use according to claim 19, wherein the respiratory disease comprises: acute sinusitis, chronic sinusitis, sinusitis operation inflammation, acute and chronic bronchitis, pneumonia, bronchiectasis, lung abscess, chronic obstructive pulmonary disease, pulmonary fungal infection, pulmonary tuberculosis, and silicosis.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910036486.7A CN109528649B (en) | 2019-01-15 | 2019-01-15 | Self-emulsifying oral preparation of terpene pharmaceutical composition, preparation method and application |
| CN2019100364867 | 2019-01-15 | ||
| PCT/CN2019/119346 WO2020147416A1 (en) | 2019-01-15 | 2019-11-19 | Terpene pharmaceutical composition self-emulsifying oral preparation, preparation method therefor and use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113329736A CN113329736A (en) | 2021-08-31 |
| CN113329736B true CN113329736B (en) | 2023-01-13 |
Family
ID=65835383
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910036486.7A Active CN109528649B (en) | 2019-01-15 | 2019-01-15 | Self-emulsifying oral preparation of terpene pharmaceutical composition, preparation method and application |
| CN201980087982.3A Active CN113329736B (en) | 2019-01-15 | 2019-11-19 | Self-emulsifying oral preparation of terpene medicinal composition, its preparation method and application |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910036486.7A Active CN109528649B (en) | 2019-01-15 | 2019-01-15 | Self-emulsifying oral preparation of terpene pharmaceutical composition, preparation method and application |
Country Status (2)
| Country | Link |
|---|---|
| CN (2) | CN109528649B (en) |
| WO (1) | WO2020147416A1 (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109528649B (en) * | 2019-01-15 | 2021-06-29 | 北京远大九和药业有限公司 | Self-emulsifying oral preparation of terpene pharmaceutical composition, preparation method and application |
| CN112704674B (en) * | 2019-10-25 | 2024-03-12 | 北京远大九和药业有限公司 | A pharmaceutical oral emulsion, and its preparation method and application |
| CN112791120B (en) * | 2019-10-25 | 2023-08-01 | 北京远大九和药业有限公司 | A pharmaceutical oral emulsion, and its preparation method and application |
| CN113018457B (en) * | 2019-12-25 | 2022-09-02 | 北京远大九和药业有限公司 | Cyclodextrin inclusion compound and preparation method thereof |
| CN113116856B (en) * | 2019-12-31 | 2023-01-13 | 北京远大九和药业有限公司 | Eucalyptus and pinene enteric-coated microspheres and preparation method thereof |
| CN114642635B (en) * | 2020-12-18 | 2023-06-30 | 北京远大九和药业有限公司 | Oral emulsion of terpene medicine composition and preparation method and application thereof |
| CN114796167B (en) * | 2021-01-29 | 2023-09-29 | 北京远大九和药业有限公司 | Inhalation preparation of terpene pharmaceutical composition and preparation method thereof |
| CN113068705B (en) * | 2021-03-26 | 2021-09-28 | 江南大学 | Preparation method of eucalyptol emulsion and application of eucalyptol emulsion in biopesticide |
| CN113181262B (en) * | 2021-04-15 | 2022-07-08 | 江西中医药大学 | Preparation for improving respiratory system diseases, pretreatment method and application |
| CN115887425A (en) * | 2022-12-08 | 2023-04-04 | 广州国家实验室 | Pharmaceutical composition, preparation method and application |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101254237A (en) * | 2008-04-10 | 2008-09-03 | 北京九和药业有限公司 | Preparation of pharmaceutical combination enteric soft capsules containing eucalyptol, limonene and a-pinene |
| CN101590033A (en) * | 2009-07-01 | 2009-12-02 | 北京九和药业有限公司 | The medicinal composition fat emulsion injection and the preparation method that contain eucalyptol, limonene and a-pinene |
| CN103893165A (en) * | 2014-03-27 | 2014-07-02 | 北京九和药业有限公司 | Nebulizer for treating respiratory system diseases |
| CN108078975A (en) * | 2017-12-29 | 2018-05-29 | 北京九和药业有限公司 | Application of the pharmaceutical composition containing eucalyptol, limonene and australene in the drug for preparing treatment upper respiratory tract bacterium infection |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105708797B (en) * | 2014-12-05 | 2020-03-17 | 天士力医药集团股份有限公司 | Self-emulsifying drug delivery system for replacing cinnamamide derivative |
| CN105395492B (en) * | 2015-11-23 | 2018-05-25 | 河南大学 | A kind of volatile oil solid self-emulsifying tablet and preparation method thereof |
| IL246790A0 (en) * | 2016-07-14 | 2016-09-29 | Friedman Doron | Self-emulsifying compositions of cannabinoids |
| CN107929394B (en) * | 2018-01-17 | 2021-01-26 | 信阳农林学院 | Oral solid self-emulsifying dispersion for treating respiratory diseases of livestock and poultry |
| CN109528649B (en) * | 2019-01-15 | 2021-06-29 | 北京远大九和药业有限公司 | Self-emulsifying oral preparation of terpene pharmaceutical composition, preparation method and application |
-
2019
- 2019-01-15 CN CN201910036486.7A patent/CN109528649B/en active Active
- 2019-11-19 CN CN201980087982.3A patent/CN113329736B/en active Active
- 2019-11-19 WO PCT/CN2019/119346 patent/WO2020147416A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101254237A (en) * | 2008-04-10 | 2008-09-03 | 北京九和药业有限公司 | Preparation of pharmaceutical combination enteric soft capsules containing eucalyptol, limonene and a-pinene |
| CN101590033A (en) * | 2009-07-01 | 2009-12-02 | 北京九和药业有限公司 | The medicinal composition fat emulsion injection and the preparation method that contain eucalyptol, limonene and a-pinene |
| CN103893165A (en) * | 2014-03-27 | 2014-07-02 | 北京九和药业有限公司 | Nebulizer for treating respiratory system diseases |
| CN108078975A (en) * | 2017-12-29 | 2018-05-29 | 北京九和药业有限公司 | Application of the pharmaceutical composition containing eucalyptol, limonene and australene in the drug for preparing treatment upper respiratory tract bacterium infection |
Non-Patent Citations (1)
| Title |
|---|
| Preparation and protective effects of 1,8-cineole-loaded self microemulsifying drug delivery system on lipopolysaccharide-induced endothelial injury in mice;Feng Jiang等;《European Journal of Pharmaceutical Sciences》;20181015;14-23 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109528649B (en) | 2021-06-29 |
| WO2020147416A1 (en) | 2020-07-23 |
| CN109528649A (en) | 2019-03-29 |
| CN113329736A (en) | 2021-08-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113329736B (en) | Self-emulsifying oral preparation of terpene medicinal composition, its preparation method and application | |
| Talegaonkar et al. | Microemulsions: a novel approach to enhanced drug delivery | |
| EP2600838B1 (en) | Pharmaceutical dosage form comprising 6'-fluoro-(n-methyl- or n,n-dimethyl-)-4-phenyl-4',9'-dihydro-3'h-spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine | |
| EP2062571B1 (en) | Self-emulsifying pharmaceutical composition with enhanced bioavailability | |
| US20020160049A1 (en) | Emulsions as solid dosage forms for oral administration | |
| US8252326B2 (en) | Self-microemulsifying dosage forms of low solubility active ingredients such as co-enzyme Q10 | |
| CN107184549B (en) | Nintedanib self-microemulsion preparation, soft capsule prepared from same and preparation method of soft capsule | |
| CN104224711B (en) | Paclitaxel submicron emulsion taking steroid compound as intermediate vector | |
| EP1249230B1 (en) | Microemulsion-preconcentrates and microemulsions comprising coenzyme Q10 | |
| EP1334717B1 (en) | Pharmaceutical Compositions For Oral And Topical Administration | |
| CN101703468A (en) | Nano-emulsion of vitamin E oil and preparation method thereof | |
| JPS6230965B2 (en) | ||
| CN101612121A (en) | The preparation of microemulsion containing paclitaxel method | |
| CN107921017A (en) | The method treated using cadotril composition | |
| EP1227793A1 (en) | Cyclosporin formulation | |
| EP1648517A1 (en) | Self-emulsifying and self-microemulsifying formulations for the oral administration of taxoids | |
| JPH01249716A (en) | Fatty emulsion of fine particle | |
| CN114642635B (en) | Oral emulsion of terpene medicine composition and preparation method and application thereof | |
| AU2859801A (en) | Pharmaceutical compositions for oral administration | |
| WO2023278708A1 (en) | Methods for treatment of pain with cannabinoids | |
| US20060233842A1 (en) | Microemulsion composition for oral administration of biphenyldimethyldicarboxylate | |
| US20200360286A1 (en) | Self-emulsifying cannabidiol formulations | |
| CN116920105A (en) | Terpene pharmaceutical composition self-emulsifying solution and preparation method thereof | |
| WO2023278665A1 (en) | Methods for treatment of opioid use disorder with cannabinoids | |
| JP2003261442A (en) | Soft capsule preparation containing pseudoephedrine hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |