WO2012113116A1 - Emulsion containing hydrophilic biological macromolecule, preparation method and application thereof - Google Patents
Emulsion containing hydrophilic biological macromolecule, preparation method and application thereof Download PDFInfo
- Publication number
- WO2012113116A1 WO2012113116A1 PCT/CN2011/000814 CN2011000814W WO2012113116A1 WO 2012113116 A1 WO2012113116 A1 WO 2012113116A1 CN 2011000814 W CN2011000814 W CN 2011000814W WO 2012113116 A1 WO2012113116 A1 WO 2012113116A1
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- WO
- WIPO (PCT)
- Prior art keywords
- weight
- parts
- vitamin
- emulsion
- polyethylene glycol
- Prior art date
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- 239000000839 emulsion Substances 0.000 title claims abstract description 81
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 229920002521 macromolecule Polymers 0.000 title claims abstract 4
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims abstract description 67
- 229940046009 vitamin E Drugs 0.000 claims abstract description 35
- 239000011709 vitamin E Substances 0.000 claims abstract description 35
- 229930003427 Vitamin E Natural products 0.000 claims abstract description 32
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims abstract description 32
- 235000019165 vitamin E Nutrition 0.000 claims abstract description 32
- -1 ester derivatives of vitamin E Chemical class 0.000 claims abstract description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 12
- 239000012071 phase Substances 0.000 claims abstract description 11
- 239000002202 Polyethylene glycol Substances 0.000 claims description 32
- 229920001223 polyethylene glycol Polymers 0.000 claims description 32
- 239000003814 drug Substances 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 239000004530 micro-emulsion Substances 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 15
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 15
- 210000004369 blood Anatomy 0.000 claims description 14
- 239000008280 blood Substances 0.000 claims description 14
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 14
- 239000008346 aqueous phase Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- OGBMKVWORPGQRR-UMXFMPSGSA-N teriparatide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 OGBMKVWORPGQRR-UMXFMPSGSA-N 0.000 claims description 13
- 239000003921 oil Substances 0.000 claims description 12
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 12
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 claims description 11
- 101000976075 Homo sapiens Insulin Proteins 0.000 claims description 11
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 claims description 11
- 108020004707 nucleic acids Proteins 0.000 claims description 11
- 102000039446 nucleic acids Human genes 0.000 claims description 11
- 150000007523 nucleic acids Chemical class 0.000 claims description 11
- 235000019198 oils Nutrition 0.000 claims description 11
- 239000008347 soybean phospholipid Substances 0.000 claims description 11
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000004359 castor oil Substances 0.000 claims description 10
- 235000019438 castor oil Nutrition 0.000 claims description 10
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- 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 10
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 10
- 229940051841 polyoxyethylene ether Drugs 0.000 claims description 10
- 229920000056 polyoxyethylene ether Polymers 0.000 claims description 10
- 229960003773 calcitonin (salmon synthetic) Drugs 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
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- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 claims description 8
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
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Classifications
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/24—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
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- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- the invention belongs to the field of pharmacy and preparation, and relates to an emulsion containing a hydrophilic biomolecule, a preparation method thereof and use thereof. Background technique
- Hydrophilic biomacromolecules including proteins or peptides, polysaccharides, and nucleic acids, are an increasingly important class of drugs in the pharmaceutical field.
- oral administration is ineffective and clinically needed. Frequent injection administration. Therefore, it is a common ideal in the medical field to develop a drug delivery system that is highly patient-compliant and suitable for oral administration.
- Oral insulin microemulsion bioavailability is only 4.44% (Amani Elsayed, et al, European Journal of Pharmaceutics and Biopharmaceutics 73 (2009) 269 - 279 ); oral PTH formulation bioavailability is only 2.1% ( Andrea Leone-Bay, et Al, Pharmaceutical Research, Vol. 18, No. 7, 2001).
- Vitamin E also known as tocopherol, is a common fat-soluble vitamin E. When used as an antioxidant, the concentration is generally less than 1%. Vitamin E is also often used as a nutritional supplement for a wide range of applications in health care, food, medical, and beauty. Due to its special structure, vitamin E has good solubility for some hydrophobic molecules such as paclitaxel, cyclosporine and body substances. According to this, Constantinides et al., in addition to “water-soluble” and “oil-soluble”, The concept of "vitamin E dissolution” (Constantinides, PP, et al. (2004) Adv Drug Deliv Rev. 56: 175-82).
- Vitamin E is highly safe as a food-borne substance and a nutritional supplement. However, the current study only uses vitamin E as a carrier for hydrophobic drugs. Vitamin E has not yet been used to achieve oral administration of hydrophilic biomacromolecules. Report of the drug. Summary of the invention
- the inventors have conducted extensive experiments and creative labor to obtain an emulsion containing a hydrophilic biomacromolecule in which an ester derivative of vitamin E or vitamin E is used as a carrier of a hydrophilic biomacromolecules.
- Vitamin E or its ester derivatives are not toxic by themselves, and can effectively solve the safety hazards of currently administered hydrophilic biomacromolecules.
- the present inventors have surprisingly found that the use of an ester derivative of vitamin E or vitamin E as a carrier for the administration of a hydrophilic biomacromolecule can significantly improve the oral bioavailability of these hydrophilic biomacromolecules.
- An emulsion containing a hydrophilic biomacromolecule comprising a hydrophilic biomacromolecule, an aqueous phase, an oil phase, an emulsifier, characterized in that the emulsion further comprises an ester derivative of vitamin E and/or vitamin E .
- hydrophilic biomacromolecule is selected from the group consisting of a protein or a polypeptide, a polysaccharide, and a nucleic acid.
- the hydrophilic biomolecule can be isolated from a living organism, or can be obtained by genetic engineering or organic synthesis.
- the emulsion according to any one of the present invention wherein the vitamin E is one or more selected from the group consisting of d- ⁇ -vitamin E and d- ⁇ -vitamin E, and the vitamin oxime ester derivative
- the substance is selected from the group consisting of d-a-vitamin E acetate, dl-a-tocopheryl acetate, da-vitamin E succinate, d-a-vitamin E succinate, da-vitamin E succinic acid polyethylene glycol One or more of an ester, and a polyethylene glycol dl-a-tocopheryl succinate.
- the ester derivative of vitamin E or vitamin E in the present invention may be natural or artificially synthesized.
- the emulsion according to any one of the present invention wherein the hydrophilic biomacromolecule is 0.01 to 1 part by weight, and the ester derivative of the vitamin E and/or vitamin E is 50 - 1 Q0G parts by weight, 50 - 5 QQ parts by weight, or 100 - 300 parts by weight.
- emulsion according to any one of the invention wherein the aqueous phase, the oil phase, and the emulsifier are 20 - 2000 parts by weight, 20 - 1000 parts by weight, or 50 - 500 parts by weight in total.
- the amount of each of the aqueous phase, the oil phase, and the emulsifier can be readily determined by those skilled in the art.
- the emulsion according to any one of the present invention wherein the protein or polypeptide is selected from the group consisting of calcitonin, insulin, GLP-1 (glucagon-like peptide-1), parathyroid hormone, and growth hormone
- the polysaccharide is selected from the group consisting of heparin, low molecular weight heparin (average molecular weight of 4000-6000), chondroitin sulfate, keratan sulfate, and hyaluronic acid
- the nucleic acid is selected from the group consisting of an antisense nucleic acid, a ribozyme, an interfering RNA, and a DECOY nucleic acid.
- the calcitonin is salmon calcitonin, salmon calcitonin, or human calcitonin
- the insulin is porcine insulin, bovine insulin, or human insulin
- the gland hormone is human parathyroid hormone 1-84, or human parathyroid hormone 1-34, and the growth hormone is porcine growth hormone, bovine growth hormone, or human growth hormone.
- aqueous phase is one or more selected from the group consisting of water, physiological saline, and an aqueous phase buffer.
- emulsifier is selected from the group consisting of soy lecithin, egg yolk lecithin, poloxamer 188, poloxamer 407, carbomer, tween 20, spit Warm 80, polyethylene glycol dodecyl stearate, polyoxyethylene ether (35) castor oil, polyoxyethylene ether (40) hydrogenated castor oil, polyglycerol-6-dioleate, polyglycerol-3 - oleate, polyethylene glycol-32-lauric acid glyceride, polyethylene glycol-32-stearic acid One or more of a glyceride, and a polyethylene glycol caprylic/capric glyceride.
- the medium chain fatty acid glyceride may be one or more of a medium chain fatty acid monoglyceride, a medium chain fatty acid diglyceride, and a medium chain fatty acid triglyceride.
- the medium chain fatty acid in the medium chain fatty acid glyceride may be bonded to any one or more hydroxyl positions in the glycerol molecule, and when forming a medium chain fatty acid diglyceride or a medium chain fatty acid triglyceride, the hydroxyl group in the glycerol molecule
- the bound medium chain fatty acid molecules can be the same or different.
- the medium chain fatty acid means a fatty acid having 6 to 12 carbon atoms, which may be saturated or unsaturated, and may be linear or branched.
- the medium chain fatty acid is octanoic acid and/or citric acid.
- any of the emulsions of the present invention further comprising a pH adjusting agent, a P H adjusting agent selected from hydrochloric acid, lactic acid, acetic acid, citric acid, phosphoric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate One or more of disodium hydrogen phosphate and sodium dihydrogen phosphate.
- Microemulsion is an isotropic, transparent, thermodynamically stable dispersion consisting of water, oil, or emulsifier, usually having a particle size of less than 500 nm.
- hydrophilic biopolymer-containing emulsion An emulsion according to any one of the invention, which is administered orally.
- the components and contents of the hydrophilic biopolymer-containing emulsion are as follows:
- Oleic acid 0.3 parts by weight
- the invention further relates to the use of the emulsion in the manufacture of a medicament for the treatment or prevention of osteoporosis.
- the invention further relates to a method of treating or preventing osteoporosis comprising the step of administering an effective amount of the emulsion.
- the components and levels of the hydrophilic biomacromer-containing emulsion are as follows:
- Polyethylene glycol octanoate / glyceryl citrate eg 2.5-3.5 parts by weight Sofitgen® 767, SAS0L
- the invention further relates to the use of the emulsion in the manufacture of a medicament for the treatment or prevention of diabetes, or for the reduction of blood sugar.
- the invention further relates to a method of treating or preventing diabetes, or lowering blood glucose, comprising the step of administering an effective amount of the emulsion.
- the components and contents of the hydrophilic biomacromer-containing emulsion are as follows:
- Recombinant human insulin 0.04 parts by weight 1 part by weight of sodium hydroxide in deionized water
- Dl- ⁇ -vitamin E acetate 1 weight * part medium chain fatty acid glyceride (eg Labrafac 0.5 parts by weight
- Polyethylene glycol caprylic acid / glyceryl citrate (for example, 3 parts by weight)
- Soy lecithin 0.5 weight The invention further relates to the use of the emulsion in the manufacture of a medicament for the treatment or prevention of diabetes, or for lowering blood glucose.
- the components and contents of the hydrophilic biomacromer-containing emulsion are as follows:
- the invention further relates to the use of the emulsion in the manufacture of a medicament for the treatment or prevention of diabetes, or for the reduction of blood sugar.
- the invention further relates to a method of treating or preventing diabetes, or lowering blood glucose, comprising the step of administering an effective amount of the emulsion.
- the components and levels of the hydrophilic biomacromer-containing emulsion are as follows:
- the present invention also relates to the use of the emulsion in the preparation of a medicament for treating or preventing osteoporosis.
- the invention further relates to a method of treating or preventing osteoporosis comprising the step of administering an effective amount of the emulsion.
- the components and contents of the hydrophilic biopolymer-containing emulsion are as follows:
- Dl- ⁇ -vitamin ⁇ 0.7 parts by weight of d- ⁇ -vitamin succinic acid polyethylene glycol ester 0.5 parts by weight of soybean oil 1.2 parts by weight of soybean lecithin 0.7 parts by weight of polyoxyethylene ether (40) hydrogenated castor oil 3 parts by weight Ethylene glycol 400 2 parts by weight.
- the invention further relates to the use of the emulsion in the manufacture of a medicament for the treatment or prevention of osteoporosis, in a particular embodiment of the invention, the hydrophilic biological fraction 0 ⁇
- the invention also relates to the use of the emulsion in the manufacture of a medicament for anticoagulation and or thrombolysis.
- the invention further relates to a method of treating or preventing a thrombus, or anticoagulation, comprising the step of administering an effective amount of the emulsion.
- the components and contents of the hydrophilic biopolymer-containing emulsion are as follows:
- the present invention is a glycerol phthalic acid glyceride.
- the method for preparing a hydrophilic biomacromer-containing emulsion according to any one of the present invention comprises the steps of:
- step 3 At 4 - 37. Under the condition of C, the product of step 1) is added dropwise to the product of step 2), and stirring is continued at 200 - 800 rpm until a clear and clear homogeneous preparation is formed, and finally a hydrophilic biomacromolecular emulsion is obtained. Still another aspect of the present invention relates to the use of the hydrophilic biomacromer-containing emulsion of the present invention for the preparation of a medicament for treating or preventing diabetes, or lowering blood glucose, wherein the hydrophilic biomacromolecule is insulin or GLP- 1.
- Still another aspect of the present invention relates to the use of the hydrophilic biomacromolecular-containing emulsion of the present invention for the preparation of a medicament for treating or preventing osteoporosis, wherein the hydrophilic biomacromolecule is calcitonin or scorpion Parathyroid hormone, parathyroid hormone 1-84, or human parathyroid hormone 1-34.
- a further aspect of the invention relates to the use of an ester derivative of vitamin E and/or vitamin E for the preparation of a hydrophilic biomolecular-containing emulsion.
- the hydrophilic biomacromer-containing emulsion is the hydrophilic biomacromolecular emulsion according to any one of the inventions.
- the vitamin E is one or more selected from the group consisting of d- ⁇ -vitamin E and cU-a-vitamin E
- the ester derivative of the vitamin E is selected from the group consisting of da-vitamin E acetate.
- d a-vitamin E acetate, d-a-tocopheryl succinate, d-a-vitamin E succinate, d-a-vitamin E succinate, and d la-vitamin E amber One or more of acid polyethylene glycol esters.
- the hydrophilic biomacromolecule and the aqueous phase, the oil phase, the emulsifier, the pH adjuster, and the like, and the amounts thereof are as described above.
- oral administration of a hydrophilic biomacromolecular drug is achieved by means of an ester derivative of vitamin E and/or vitamin E, and is safe, effective, and has high oral bioavailability, and bioavailability. Degree can reach 5%, 10%, 12%, 15% or even 30%;
- the prepared vitamin E microemulsion containing a hydrophilic bio-low molecular drug can spontaneously emulsify into a droplet of 300 nm or less after being in contact with water, and is better absorbed and utilized by the gastrointestinal tract to exert better biological activity.
- Fig. 1 Diagram of blood glucose changes in rats under different modes of administration.
- Fig. 2 Phase diagram of plasma concentration of rat PTH1-34 under different modes of administration. detailed description
- Example 1 Preparation of an emulsion containing salmon calcitonin (microemulsion)
- D- ⁇ -vitamin E 0.7 g oleic acid Q.3 g polyethylene glycol dodecyl stearate (Solutol 1.5 g
- step 3 30. Under C, add the A solution dropwise to the product of step 2), stir the mixture to a clear and clear at 800 r/min, and finally obtain an emulsion (microemulsion) containing salmon calcitonin (called sample 1). ).
- Example 2 Preparation of emulsion containing recombinant human insulin (microemulsion)
- Poloxamer 188 (Lutrol F68, BASF) 0.2 g
- Soy lecithin (Epikuron 170, Degussa) 0.5 g.
- Example 3 Preparation of an emulsion containing GLP-1 (microemulsion)
- TPGS d- ⁇ -Vitamin E succinic acid polyethylene glycol ester
- Example 4 Preparation of an emulsion containing PTH 1-34 (microemulsion)
- TPGS D- ⁇ -vitamin succinic acid polyethylene glycol ester
- Soy lecithin (Epikuron 170, Degussa) 0 ⁇ 7 g
- step 3 Add the A solution dropwise to the product of step 2) at 30 ° C, and continue stirring at 500 r / min to clear and clear, and finally obtain a PTH 1-34 containing emulsion (microemulsion) ( Called sample 4).
- Example 5 Preparation of emulsion containing low molecular weight heparin (microemulsion)
- Polyethylene glycol 400 0.5 g.
- step 3 Add the A solution dropwise to the product of step 2) at 30 ° C, and continue stirring at 500 r / min to clear and clear, and finally obtain an emulsion (microemulsion) containing low molecular weight heparin. For sample 5).
- Example 6 Preparation of an emulsion containing small interfering RNA (microemulsion) The composition is as follows:
- Dg- ⁇ -vitamin E 0. 2 g Polyglycerol-3-oleate 0. 3 g Polyethylene glycol octanoic acid / glyceryl citrate 2. 7 g Glycerol 0. 5 g.
- sample 6 an emulsion (microemulsion) containing small molecule interference RNA (referred to as sample 6) was obtained.
- Example 6 Particle size measurement test
- Example 8 Efficacy test of emulsion containing recombinant human insulin (microemulsion) Oral test group: 6 male SD rats in the range of 180 - 220 g, drug (test drug) was sample 2 prepared in Example 2.
- Oral control group 6 male Sprague-Dawley rats in the range of 180-220 g, the drug (control drug) was prepared according to the composition and procedure of Example 2, except that no d- ⁇ -vitamin oxime acetate was added.
- Intravenous control group 6 male Sprague-Dawley rats in the range of 180-220 g, the drug was an aqueous insulin solution.
- Rats in the experimental group were anesthetized with sodium pentobarbital at a dose of 50 rag before the test, then bundled in the supine position, and cut into a small mouth in the abdomen, and administered to the ileum by the applicator. After that, suture the incision.
- the control group was administered subcutaneously as a control drug, and the dose was 0.04 mg/kg based on the insulin.
- the three groups were all taken from the tail vein at the time of 0.5, 1, 2, 3, and 4 h after administration.
- the blood glucose was measured using a Roche blood glucose meter and the average blood glucose level of 6 rats in each group was calculated.
- Figure 1 As can be seen from Fig. 1, the bioavailability of the test group administered orally was 12.5% relative to the control group administered by injection.
- Example 9 Emulsion containing PTH1-34 (microemulsion) Bioavailability test Test group: 10 male SD rats in the range of 180 - 220 g, and the drug (test drug) was the sample prepared in Example 4.
- Control group 10 male SD rats in the range of 180-220 g, the drug was PTH1-34 aqueous solution, and administered by injection.
- mice Male SD rats weighing 180-220 g were fasted for 12 h before starting the test.
- the test group was orally administered, and the dose was 10 ( ⁇ g/kg) according to PTH1-34.
- the animals in the oral group were anesthetized with sodium pentobarbital at a dose of 50 mg before the experiment, and then tied in an upright manner. A small opening was made in the abdomen, and the ileum was administered by the applicator. After the administration, the incision was sutured.
- the control group was subcutaneously injected with PTH1-34, and the dose was 10 g/kg as PTH1-34.
- the blood was taken from the tail vein at the time points of 15, 30, 45, 60, 75, 90, and 105 minutes after administration, and the serum was separated for testing.
- Serum PTH 1-34 concentrations were measured using the PTH 1-34 high sensitivity EIA kit. The results are shown in Figure 2, where the area under the PTH1-3 blood concentration curve is calculated. 2% ⁇ The bioavailability of the test group administered orally was 23.13%.
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Abstract
An emulsion containing hydrophilic biological macromolecule, preparation method and application thereof are provided. The emulsion contains hydrophilic biological macromolecule, water phase, oil phase, emulsifying agent, vitamin E and/or ester derivatives of vitamin E.
Description
含亲水性生物大分子的乳剂、 其制备方法及用途 技术领域 Emulsion containing hydrophilic biomacromolecules, preparation method and use thereof
本发明属于药物学和制剂学领域, 涉及一种含亲水性生物大 分子的乳剂、 其制备方法及用途。 背景技术 The invention belongs to the field of pharmacy and preparation, and relates to an emulsion containing a hydrophilic biomolecule, a preparation method thereof and use thereof. Background technique
胰岛素为代表的亲水性生物大分子药物, 包括蛋白质或多肽、 多糖、 核酸, 是药物领域中日益重要的一类药物, 但这类物质的一 个共同特点是, 口服给药无效, 临床中需要频繁的注射给药。 因此, 开发一种患者依从度高、 适合口服给药的给药体系, 是医药界的共 同理想。 Hydrophilic biomacromolecules, including proteins or peptides, polysaccharides, and nucleic acids, are an increasingly important class of drugs in the pharmaceutical field. However, a common feature of these substances is that oral administration is ineffective and clinically needed. Frequent injection administration. Therefore, it is a common ideal in the medical field to develop a drug delivery system that is highly patient-compliant and suitable for oral administration.
几十年来, 研究人员采用共价修饰、 酶抑制剂、 吸收促进剂、 微嚢微球包裹、 W/0 (油包水)乳剂等策略, 以期解决这些亲水性 生物大分子药物口服生物利用度低的问题。 Carino G.P. et al (2000) J. Control. Release. 65: 261-269; Kathryn Wehitehead, et al (2004) J. Control. Release. 98: 37-45; Yan Pan, et al (2002) Int. J. Pharm 249: 139-147; Nerurkar M. M. et al (1996) Pharm. Res. 13: 528-534; Marschutz M. K. et al (2000) Biomaterials 21: 1499-1507; Christopher J. H. et al (1997) Adv. Drug. Deliver. Rev. 25: 71-89; Jeff Wang, et al (2003) J. Control. Release. 88: 369-380; Roger R. C. New, et al (1997) Adv. Drug. Deliver. Rev. 25: 59-69; Anja Graf, et al (2008) Int. J. Pharm. 350: 351-360; R. Neslihan Gursoy et al (2004) Biomed. Pharmacother. 58: 173-182; CN01115327. X, US4849405, US58246380
但是上述常规的解决亲水物质口服给药方法的安全隐患, 例 如:共价修饰会降低药物活性,并可能改变药物分子的药理、毒理, 带来严重的安全隐患; 酶抑止剂, 长期服用将造成消化吸收紊乱甚 至胰脏的肿大或增生; 吸收促进剂有可能对细胞膜造成不可逆的破 坏, 长期服用会导致膜中毒。 For decades, researchers have used strategies such as covalent modification, enzyme inhibitors, absorption enhancers, microsphere microspheres, and W/0 (water-in-oil) emulsions to address the oral bioavailability of these hydrophilic biomacromolecules. Low problem. Carino GP et al (2000) J. Control. Release. 65: 261-269; Kathryn Wehitehead, et al (2004) J. Control. Release. 98: 37-45; Yan Pan, et al (2002) Int. J Pharm 249: 139-147; Nerurkar MM et al (1996) Pharm. Res. 13: 528-534; Marschutz MK et al (2000) Biomaterials 21: 1499-1507; Christopher JH et al (1997) Adv. Drug. Deliver. Rev. 25: 71-89; Jeff Wang, et al (2003) J. Control. Release. 88: 369-380; Roger RC New, et al (1997) Adv. Drug. Deliver. Rev. 25: 59 -69; Anja Graf, et al (2008) Int. J. Pharm. 350: 351-360; R. Neslihan Gursoy et al (2004) Biomed. Pharmacother. 58: 173-182; CN01115327. X, US4849405, US5824638 0 However, the above-mentioned conventional safety problems for the oral administration of hydrophilic substances, for example, covalent modification may reduce the activity of the drug, and may change the pharmacology and toxicology of the drug molecule, causing serious safety hazards; enzyme inhibitors, long-term use It will cause digestive and absorption disorders and even enlargement or hyperplasia of the pancreas; absorption enhancers may cause irreversible damage to the cell membrane, and long-term use may cause membrane poisoning.
此外, 目前已经报道的关于生物大分子的口服生物利用度的数 据并不理想。 口服胰岛素微乳剂生物利用度仅为 4.44% (Amani Elsayed , et al, European Journal of Pharmaceutics and Biopharmaceutics 73 (2009) 269 - 279 ) ; 口服 PTH制剂生物利 用度仅为 2.1% ( Andrea Leone-Bay, et al , Pharmaceutical Research, Vol. 18, No. 7, 2001 ) 。 In addition, data on oral bioavailability of biomacromolecules that have been reported so far are not ideal. Oral insulin microemulsion bioavailability is only 4.44% (Amani Elsayed, et al, European Journal of Pharmaceutics and Biopharmaceutics 73 (2009) 269 - 279 ); oral PTH formulation bioavailability is only 2.1% ( Andrea Leone-Bay, et Al, Pharmaceutical Research, Vol. 18, No. 7, 2001).
维生素 E, 又称生育酚, 是一种常见的脂溶性维生素 E。 当作 为抗氧化剂使用时, 浓度一般小于 1%。维生素 E也常被作为营养补 充剂, 广泛应用在保健、 食品、 医疗、 美容等领域。 维生素 E因其 特殊的结构, 对紫杉醇、 环孢素、 体类物质等一些疏水分子, 有 着很好的溶解性, Constantinides等人据此,在 "水溶" 、 "油溶" 之外,又提出了 "维生素 E溶" 的概念(Constantinides, P. P., et al. ( 2004 ) Adv Drug Deliv Rev. 56: 175-82 ) 。 Vitamin E, also known as tocopherol, is a common fat-soluble vitamin E. When used as an antioxidant, the concentration is generally less than 1%. Vitamin E is also often used as a nutritional supplement for a wide range of applications in health care, food, medical, and beauty. Due to its special structure, vitamin E has good solubility for some hydrophobic molecules such as paclitaxel, cyclosporine and body substances. According to this, Constantinides et al., in addition to "water-soluble" and "oil-soluble", The concept of "vitamin E dissolution" (Constantinides, PP, et al. (2004) Adv Drug Deliv Rev. 56: 175-82).
以维生素 E为溶剂, 应用于疏水分子的新型给药载体, 最先见 于 Y. Kato等人的研究,随后相关的研究层出不穷(Y. Kato, et al. (1993) Chem. Pharm. Bull. (Tokyo) . 41: 599 - 604; Constantinides, P.P., et al. ( 2000 )Pharm Res. 17: 175-82; P. B. Nielsen, et al. (2001) Int. J. Pharm. 222: 217-24; Constantinides, P.P., et al. ( 2006 ) Pharm Res. 23: 243-55; WO 95/11039; WO97/03651; WO 99/04787; US 6,479,540; US 6, 458, 373; US7030155B2 ) 。
维生素 E作为食源性物质和营养补充剂, 有着高度的安全性, 但是目前的研究仅将维生素 E作为疏水药物的载体, 尚未见到利用 维生素 E实现亲水性生物大分子药物的口服化给药的报道。 发明内容 A new drug delivery vector for hydrophobic molecules using vitamin E as a solvent was first seen in the study by Y. Kato et al., and subsequent research has emerged in an endless stream (Y. Kato, et al. (1993) Chem. Pharm. Bull. ( Tokyo) . 41: 599 - 604; Constantinides, PP, et al. (2000) Pharm Res. 17: 175-82; PB Nielsen, et al. (2001) Int. J. Pharm. 222: 217-24; Constantinides , PP, et al. (2006) Pharm Res. 23: 243-55; WO 95/11039; WO97/03651; WO 99/04787; US 6,479,540; US 6, 458, 373; US7030155B2). Vitamin E is highly safe as a food-borne substance and a nutritional supplement. However, the current study only uses vitamin E as a carrier for hydrophobic drugs. Vitamin E has not yet been used to achieve oral administration of hydrophilic biomacromolecules. Report of the drug. Summary of the invention
本发明人经过大量的试验和创造性地劳动, 得到了一种含亲 水性生物大分子的乳剂, 其中, 使用维生素 E或维生素 E的酯类 衍生物作为亲水性生物大分子的载体。 维生素 E或其酯类衍生物 本身无毒, 可以有效解决目前口服给药的亲水性生物大分子药物 的安全隐患问题。 本发明人惊奇地发现, 将维生素 E或维生素 E 的酯类衍生物作为亲水性生物大分子的给药载体, 能显著提高这 些亲水性生物大分子药物的口服生物利用度。 The inventors have conducted extensive experiments and creative labor to obtain an emulsion containing a hydrophilic biomacromolecule in which an ester derivative of vitamin E or vitamin E is used as a carrier of a hydrophilic biomacromolecules. Vitamin E or its ester derivatives are not toxic by themselves, and can effectively solve the safety hazards of currently administered hydrophilic biomacromolecules. The present inventors have surprisingly found that the use of an ester derivative of vitamin E or vitamin E as a carrier for the administration of a hydrophilic biomacromolecule can significantly improve the oral bioavailability of these hydrophilic biomacromolecules.
由此提供了下述发明: The following invention is thus provided:
一种含亲水性生物大分子的乳剂, 包含亲水性生物大分子、 水相、 油相、 乳化剂, 其特征在于, 所述乳剂还包含维生素 E和 / 或维生素 E的酯类衍生物。 An emulsion containing a hydrophilic biomacromolecule comprising a hydrophilic biomacromolecule, an aqueous phase, an oil phase, an emulsifier, characterized in that the emulsion further comprises an ester derivative of vitamin E and/or vitamin E .
根据本发明的任一项所述的乳剂, 其中, 所述亲水性生物大 分子选自蛋白质或多肽、 多糖、 以及核酸。 所述亲水性生物大分 子可以从生物机体中分离获得, 也可以通过基因工程手段或有机 合成方式获得。 The emulsion according to any one of the invention, wherein the hydrophilic biomacromolecule is selected from the group consisting of a protein or a polypeptide, a polysaccharide, and a nucleic acid. The hydrophilic biomolecule can be isolated from a living organism, or can be obtained by genetic engineering or organic synthesis.
根据本发明的任一项所述的乳剂, 其中, 所述维生素 E为选 自 d-α-维生素 E和 d卜 α-维生素 E中的一种或多种, 所述维生素 Ε的酯类衍生物为选自 d- a-维生素 E醋酸酯、 dl- a-维生素 E醋 酸酯、 d-a-维生素 E琥珀酸酯、 d卜 a-维生素 E琥珀酸酯、 d-a- 维生素 E琥珀酸聚乙二醇酯、 和 dl-a-维生素 E琥珀酸聚乙二醇 酯中的一种或多种。
本发明中的维生素 E或维生素 E的酯类衍生物可以是天然的, 也可以是人工合成的。 The emulsion according to any one of the present invention, wherein the vitamin E is one or more selected from the group consisting of d-α-vitamin E and d-α-vitamin E, and the vitamin oxime ester derivative The substance is selected from the group consisting of d-a-vitamin E acetate, dl-a-tocopheryl acetate, da-vitamin E succinate, d-a-vitamin E succinate, da-vitamin E succinic acid polyethylene glycol One or more of an ester, and a polyethylene glycol dl-a-tocopheryl succinate. The ester derivative of vitamin E or vitamin E in the present invention may be natural or artificially synthesized.
根据本发明的任一项所述的乳剂, 其中, 所述亲水性生物大 分子为 0. 01 - 1重量份,并且所述维生素 E和 /或维生素 E的酯类 衍生物为 50 - 1 Q0G重量份、 50 - 5 QQ重量份、 或者 100 - 300重 量份。 The emulsion according to any one of the present invention, wherein the hydrophilic biomacromolecule is 0.01 to 1 part by weight, and the ester derivative of the vitamin E and/or vitamin E is 50 - 1 Q0G parts by weight, 50 - 5 QQ parts by weight, or 100 - 300 parts by weight.
根据本发明的任一项所述的乳剂, 其中, 所述水相、 油相、 以及乳化剂合计为 20 - 2000重量份、 20 - 1000重量份、 或者 50 -500重量份。 对本领域技术人员而言, 可以容易地确定水相、 油 相、 以及乳化剂各自的量。 The emulsion according to any one of the invention, wherein the aqueous phase, the oil phase, and the emulsifier are 20 - 2000 parts by weight, 20 - 1000 parts by weight, or 50 - 500 parts by weight in total. The amount of each of the aqueous phase, the oil phase, and the emulsifier can be readily determined by those skilled in the art.
根据本发明的任一项所述的乳剂, 其中, 所述蛋白质或多肽 选自降钙素、 胰岛素、 GLP- 1 (胰高血糖素样肽- 1 )、 曱状旁腺激 素、 和生长激素; 所述多糖选自肝素、 低分子量肝素 (平均分子 量在 4000 - 6000 ) 、 硫酸软骨素、 硫酸角质素、 和透明质酸; 所 述核酸选自反义核酸、核酶、干扰 RNA、 DECOY核酸、和三链核酸; 具体地; 所述降钙素为鲑鱼降钙素、 鰻鱼降钙素、 或人降钙素; 所述胰岛素为猪胰岛素、 牛胰岛素、 或人胰岛素; 所述甲状旁腺 激素为人体甲状旁腺激素 1-84、或人甲状旁腺激素 1-34、所述生 长激素为猪生长激素、 牛生长激素、 或人生长激素。 The emulsion according to any one of the present invention, wherein the protein or polypeptide is selected from the group consisting of calcitonin, insulin, GLP-1 (glucagon-like peptide-1), parathyroid hormone, and growth hormone The polysaccharide is selected from the group consisting of heparin, low molecular weight heparin (average molecular weight of 4000-6000), chondroitin sulfate, keratan sulfate, and hyaluronic acid; the nucleic acid is selected from the group consisting of an antisense nucleic acid, a ribozyme, an interfering RNA, and a DECOY nucleic acid. And a triple-stranded nucleic acid; specifically; the calcitonin is salmon calcitonin, salmon calcitonin, or human calcitonin; the insulin is porcine insulin, bovine insulin, or human insulin; The gland hormone is human parathyroid hormone 1-84, or human parathyroid hormone 1-34, and the growth hormone is porcine growth hormone, bovine growth hormone, or human growth hormone.
根据本发明的任一项所述的乳剂, 其中, 所述水相为选自水、 生理盐水、 以及水相緩冲液中的一种或多种。 The emulsion according to any one of the present invention, wherein the aqueous phase is one or more selected from the group consisting of water, physiological saline, and an aqueous phase buffer.
根据本发明的任一项所述的乳剂, 其中, 所述乳化剂为选自 大豆卵磷脂、蛋黄卵磷脂、 泊洛沙姆 188、 泊洛沙姆 407、卡波姆、 吐温 20、 吐温 80、 聚乙二醇十二羟基硬脂酸酯、 聚氧乙烯醚(35) 蓖麻油、 聚氧乙烯醚(40)氢化蓖麻油、 聚甘油 -6-二油酸酯、 聚甘 油 -3-油酸酯、聚乙二醇- 32-月桂酸甘油酯、聚乙二醇- 32-硬脂酸
甘油酯、 以及聚乙二醇辛酸 /癸酸甘油酯中的一种或多种。 The emulsion according to any one of the invention, wherein the emulsifier is selected from the group consisting of soy lecithin, egg yolk lecithin, poloxamer 188, poloxamer 407, carbomer, tween 20, spit Warm 80, polyethylene glycol dodecyl stearate, polyoxyethylene ether (35) castor oil, polyoxyethylene ether (40) hydrogenated castor oil, polyglycerol-6-dioleate, polyglycerol-3 - oleate, polyethylene glycol-32-lauric acid glyceride, polyethylene glycol-32-stearic acid One or more of a glyceride, and a polyethylene glycol caprylic/capric glyceride.
根据本发明的任一项所述的乳剂, 其中, 所述油相为选自中 链脂肪酸甘油酯、 大豆油、玉米油、花生油、油酸、聚乙二醇 400、 甘油、 乙醇、 以及丙二醇中的一种或多种。 所述中链脂肪酸甘油 酯可以为中链脂肪酸甘油一酯、 中链脂肪酸甘油二酯、 以及中链 脂肪酸甘油三酯中的一种或多种。 所述中链脂肪酸甘油酯中的中 链脂肪酸可以结合在甘油分子中的任何一个或多个羟基位置, 当 形成中链脂肪酸甘油二酯或中链脂肪酸甘油三酯时, 甘油分子中 的羟基上结合的中链脂肪酸分子可以相同或者不同。在本发明中, 中链脂肪酸是指碳原子数 6 - 12的脂肪酸, 其可以是饱和的, 也 可以是不饱和的, 可以是直链的, 也可以是支链的。 具体地, 所 述中链脂肪酸为辛酸和 /或癸酸。 The emulsion according to any one of the present invention, wherein the oil phase is selected from the group consisting of medium chain fatty acid glycerides, soybean oil, corn oil, peanut oil, oleic acid, polyethylene glycol 400, glycerin, ethanol, and propylene glycol. One or more of them. The medium chain fatty acid glyceride may be one or more of a medium chain fatty acid monoglyceride, a medium chain fatty acid diglyceride, and a medium chain fatty acid triglyceride. The medium chain fatty acid in the medium chain fatty acid glyceride may be bonded to any one or more hydroxyl positions in the glycerol molecule, and when forming a medium chain fatty acid diglyceride or a medium chain fatty acid triglyceride, the hydroxyl group in the glycerol molecule The bound medium chain fatty acid molecules can be the same or different. In the present invention, the medium chain fatty acid means a fatty acid having 6 to 12 carbon atoms, which may be saturated or unsaturated, and may be linear or branched. Specifically, the medium chain fatty acid is octanoic acid and/or citric acid.
根据本发明的任一项所述的乳剂, 其还包含 pH调节剂, 所述 PH值调节剂选自盐酸、 乳酸、 醋酸、 枸橼酸、 磷酸、 氢氧化钠、 碳酸钠、 碳酸氢钠、 磷酸氢二钠、 以及磷酸二氢钠中的一种或多 种。 According to any of the emulsions of the present invention, further comprising a pH adjusting agent, a P H adjusting agent selected from hydrochloric acid, lactic acid, acetic acid, citric acid, phosphoric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate One or more of disodium hydrogen phosphate and sodium dihydrogen phosphate.
根据本发明的任一项所述的乳剂, 其为微乳剂。 微乳是指由 水、 油、 乳化剂组成的, 各向同性、 透明、 热力学稳定的分散体 系, 通常粒径小于 500nm。 An emulsion according to any one of the invention, which is a microemulsion. Microemulsion is an isotropic, transparent, thermodynamically stable dispersion consisting of water, oil, or emulsifier, usually having a particle size of less than 500 nm.
根据本发明的任一项所述的乳剂, 其通过口服给药。 在本发明的一个具体的实施方案中 所述含亲水性生物大分 子的乳剂的组分及含量如下: An emulsion according to any one of the invention, which is administered orally. In a specific embodiment of the invention, the components and contents of the hydrophilic biopolymer-containing emulsion are as follows:
鲑鱼降钙素 0. 001重量份 1摩尔盐酸 适量 Salmon calcitonin 0. 001 parts by weight 1 mole of hydrochloric acid
生理盐水 0. 35重量份
d-α-维生素 E 0.7重量份 Physiological saline 0. 35 parts by weight D-α-vitamin E 0.7 parts by weight
油酸 0.3重量份 Oleic acid 0.3 parts by weight
吐温 80 1.5重量份。 Tween 80 1.5 parts by weight.
本发明还涉及该乳剂在制备治疗或预防骨质疏松的药物中的 用途。 本发明还涉及一种治疗或预防骨质疏松的方法, 包括给予 有效量的该乳剂的步骤。 在本发明的一个实施方案中, 所述含亲水性生物大分子的乳 剂的组分及含量如下: The invention further relates to the use of the emulsion in the manufacture of a medicament for the treatment or prevention of osteoporosis. The invention further relates to a method of treating or preventing osteoporosis comprising the step of administering an effective amount of the emulsion. In one embodiment of the invention, the components and levels of the hydrophilic biomacromer-containing emulsion are as follows:
重组人胰岛素 0.03 - 0.05重量份 氢氧化钠 适量 Recombinant human insulin 0.03 - 0.05 parts by weight sodium hydroxide
去离子水 0.8- 1.2重量份 dl-α-维生素 E醋 0.8 - 1.2重量份 中链脂肪酸甘油酯 (例如 Labrafac 0.6- 0.7重量份 Lipophi le 1349, Gattefosse ) Deionized water 0.8-1.2 parts by weight dl-α-vitamin E vinegar 0.8 - 1.2 parts by weight Medium chain fatty acid glycerides (eg Labrafac 0.6-0.7 parts by weight Lipophi le 1349, Gattefosse )
聚乙二醇辛酸 /癸酸甘油酯 (例如 2.5- 3.5重量份 Sofitgen® 767, SAS0L) Polyethylene glycol octanoate / glyceryl citrate (eg 2.5-3.5 parts by weight Sofitgen® 767, SAS0L)
泊、洛沙姆 188 0.1 - 0.3重量份 大豆卵磷脂 0.4- 0.6重量份。 本发明还涉及该乳剂在制备治疗或预防糖尿病、 或者降低血 糖的药物中的用途。 本发明还涉及一种治疗或预防糖尿病、 或者 降低血糖的方法, 包括给予有效量的该乳剂的步骤。 在本发明的 一个具体的实施方案中, 所述含亲水性生物大分子的乳剂的组分 及含量如下: Bo, Losham 188 0.1 - 0.3 parts by weight Soy lecithin 0.4 - 0.6 parts by weight. The invention further relates to the use of the emulsion in the manufacture of a medicament for the treatment or prevention of diabetes, or for the reduction of blood sugar. The invention further relates to a method of treating or preventing diabetes, or lowering blood glucose, comprising the step of administering an effective amount of the emulsion. In a specific embodiment of the invention, the components and contents of the hydrophilic biomacromer-containing emulsion are as follows:
重组人胰岛素 0.04重量份
氢氧化钠 适量 去离子水 1重量份 Recombinant human insulin 0.04 parts by weight 1 part by weight of sodium hydroxide in deionized water
dl-α-维生素 E醋酸酯 1重 *份 中链脂肪酸甘油酯 (例如 Labrafac 0.5重量份 Dl-α-vitamin E acetate 1 weight * part medium chain fatty acid glyceride (eg Labrafac 0.5 parts by weight
Lipophile 1349, Gattef osse ) Lipophile 1349, Gattef osse )
聚乙二醇辛酸 /癸酸甘油酯 (例如 3重量份 Polyethylene glycol caprylic acid / glyceryl citrate (for example, 3 parts by weight)
Sofitgen® 767, SAS0L) Sofitgen® 767, SAS0L)
泊洛沙姆 188 0.2重 Poloxamer 188 0.2 heavy
大豆卵磷脂 0.5重
本发明还涉及该乳剂在制备治疗或预防糖尿病、 或者降低血 糖的药物中的用途。 在本发明的一个具体的实施方案中, 所述含亲水性生物大分 子的乳剂的组分及含量如下: Soy lecithin 0.5 weight The invention further relates to the use of the emulsion in the manufacture of a medicament for the treatment or prevention of diabetes, or for lowering blood glucose. In a specific embodiment of the present invention, the components and contents of the hydrophilic biomacromer-containing emulsion are as follows:
GLP-1 0.0005重量份 GLP-1 0.0005 parts by weight
PBS緩冲液 0.3重量份 d-α-维生素 E琥珀酸聚乙二醇酯 1.5重量份 聚乙二醇十二羟基硬脂酸酯 2重量份 吐温 20 0.5重量份。 本发明还涉及该乳剂在制备治疗或预防糖尿病、 或者降低血 糖的药物中的用途。 本发明还涉及一种治疗或预防糖尿病、 或者 降低血糖的方法, 包括给予有效量的该乳剂的步骤。 在本发明的一个实施方案中, 所述含亲水性生物大分子的乳 剂的组分及含量如下: PBS buffer 0.3 parts by weight d-α-tocopherol polyethylene glycol succinate 1.5 parts by weight polyethylene glycol dodecyl stearate 2 parts by weight Tween 20 0.5 parts by weight. The invention further relates to the use of the emulsion in the manufacture of a medicament for the treatment or prevention of diabetes, or for the reduction of blood sugar. The invention further relates to a method of treating or preventing diabetes, or lowering blood glucose, comprising the step of administering an effective amount of the emulsion. In one embodiment of the invention, the components and levels of the hydrophilic biomacromer-containing emulsion are as follows:
PTH 1-34 0.005 - 0.015重量份
水 (优选双蒸水) 0.4-0.6重量份 适量 PTH 1-34 0.005 - 0.015 parts by weight Water (preferably double distilled water) 0.4-0.6 parts by weight
dl-α-维生素 E 0.6 - 0.8重量份 d-α-维生素 E琥珀酸聚乙二醇酯 0.4.0.6重量份 大豆油 1.0- 1.4重量份 大豆卵磷脂 0.6-0.8重量份 聚氧乙烯醚(40)氢化蓖麻油 2.5- 3.5重量份 聚乙二醇 400 1.5-2.5重量份, 本发明还涉及该乳剂在制备治疗或预防骨质疏松的药物中的 用途。 本发明还涉及一种治疗或预防骨质疏松的方法, 包括给予 有效量的该乳剂的步驟。 Dl-α-vitamin E 0.6 - 0.8 parts by weight of d-α-tocopherol polyethylene glycolate 0.4.0.6 parts by weight of soybean oil 1.0-1.4 parts by weight of soy lecithin 0.6-0.8 parts by weight of polyoxyethylene ether (40 Hydrogenated castor oil 2.5-3.5 parts by weight of polyethylene glycol 400 1.5-2.5 parts by weight, the present invention also relates to the use of the emulsion in the preparation of a medicament for treating or preventing osteoporosis. The invention further relates to a method of treating or preventing osteoporosis comprising the step of administering an effective amount of the emulsion.
在本发明的一个具体的实施方案中, 所述含亲水性生物大分 子的乳剂的组分及含量如下: In a specific embodiment of the invention, the components and contents of the hydrophilic biopolymer-containing emulsion are as follows:
PTH 1-34 0.01重量份 水(优选双蒸水) 0.5重量份 醋酸 适量 PTH 1-34 0.01 parts by weight Water (preferably double distilled water) 0.5 parts by weight Acetic acid
dl-α-维生素 Ε 0.7重量份 d-α-维生素 Ε琥珀酸聚乙二醇酯 0.5重量份 大豆油 1.2重量份 大豆卵磷脂 0.7重量份 聚氧乙烯醚(40)氢化蓖麻油 3重量份 聚乙二醇 400 2重量份。 Dl-α-vitamin Ε 0.7 parts by weight of d-α-vitamin succinic acid polyethylene glycol ester 0.5 parts by weight of soybean oil 1.2 parts by weight of soybean lecithin 0.7 parts by weight of polyoxyethylene ether (40) hydrogenated castor oil 3 parts by weight Ethylene glycol 400 2 parts by weight.
本发明还涉及该乳剂在制备治疗或预防骨质疏松的药物中的 用途, 在本发明的一个具体的实施方案中, 所述含亲水性生物大分
低分子量肝素 0. 3重量份The invention further relates to the use of the emulsion in the manufacture of a medicament for the treatment or prevention of osteoporosis, in a particular embodiment of the invention, the hydrophilic biological fraction 0重量份
PBS緩冲液 0. 5重量份 dl-α-维生素 E 0. 2重量份 聚甘油 -3-油酸酯 1. 2重量份 吐温 8Q 1重量份 聚乙二醇辛酸 /癸酸甘油酉; 2. 7重量份 聚乙二醇 400 0. 5重量份。 本发明还涉及该乳剂在制备抗凝血和或溶栓的药物中的用 途。 本发明还涉及一种治疗或预防血栓、 或者抗凝血的方法, 包 括给予有效量的该乳剂的步骤。 在本发明的一个具体的实施方案中, 所述含亲水性生物大分 子的乳剂的组分及含量如下: 5重量份的聚含含-3-oleic acid ester 1. 2 parts by weight of Tween 8Q 1 part by weight of polyethylene glycol caprylic acid / glycerol citrate; 2重量份。 7 parts by weight of polyethylene glycol 400 0. 5 parts by weight. The invention also relates to the use of the emulsion in the manufacture of a medicament for anticoagulation and or thrombolysis. The invention further relates to a method of treating or preventing a thrombus, or anticoagulation, comprising the step of administering an effective amount of the emulsion. In a specific embodiment of the invention, the components and contents of the hydrophilic biopolymer-containing emulsion are as follows:
小分子干扰 RNA (例如大小为 500bp ) 0. 0003重量份 注射用水 0. 5重量份 Small amount of interfering RNA (for example, 500 bp) 0. 0003 parts by weight water for injection 0. 5 parts by weight
(Π-α-维生素 Ε 0. 2重量份 聚甘油 -3-油酸酯 0. 3重量份 聚乙二醇辛酸 /癸酸甘油酯 2. 7重量份 甘油 0. 5重量份。 本发明的另一方面涉及本发明的任一项所述的含亲水性生物 大分子的乳剂的制备方法, 包括下述步骤: 5重量份。 According to the present invention, the present invention is a glycerol phthalic acid glyceride. In another aspect, the method for preparing a hydrophilic biomacromer-containing emulsion according to any one of the present invention comprises the steps of:
1 ) 在 4 - 25 °C条件下, 将亲水性生物大分子溶于水相; 1) dissolving the hydrophilic biomacromolecules in the aqueous phase at 4 - 25 °C;
2 )在 20 - 70'C条件下, 将维生素 E和 /或维生素 E的酯类衍 生物与油相、 乳化剂相混合, 并在 200 - 800rmp搅拌条件下持续
搅拌, 直至整个体系呈透明清亮状; 2) Mixing the ester derivatives of vitamin E and/or vitamin E with the oil phase and emulsifier at 20 - 70 ° C and stirring at 200 - 800 rpm Stir until the entire system is clear and clear;
3 ) 在 4 - 37。C条件下, 将步骤 1 ) 产物, 逐滴加入步驟 2 ) 产物中, 并在 200 - 800rmp条件下继续搅拌, 直至形成透明清亮 的均匀制剂, 最终获得含亲水性生物大分子的乳剂。 本发明的还一方面涉及本发明的含亲水性生物大分子的乳剂 在制备治疗或预防糖尿病、或者降低血糖的药物中的用途, 其中, 所述亲水性生物大分子为胰岛素或 GLP-1。 本发明的还一方面涉及本发明的含亲水性生物大分子的乳剂 在制备治疗或预防骨质疏松的药物中的用途, 其中, 所述亲水性 生物大分子为降钙素、 曱状旁腺激素、 甲状旁腺激素 1-84、 或人 甲状旁腺激素 1-34。 本发明的还一方面涉及维生素 E和 /或维生素 E的酯类衍生物 在制备含亲水性生物大分子的乳剂中的用途。 具体地, 所述含亲 水性生物大分子的乳剂为本发明的任一项所述的含亲水性生物大 分子的乳剂。具体地,所述维生素 E为选自 d-α-维生素 E和 cU-a- 维生素 E 中的一种或多种, 所述维生素 E 的酯类衍生物为选自 d-a-维生素 E醋酸酯、 d卜 a-维生素 E醋酸酯、 d- a-维生素 E琥 珀酸酯、 d卜 a-维生素 E琥珀酸酯、 d- a-维生素 E琥珀酸聚乙二 醇酯、 和 d l-a-维生素 E琥珀酸聚乙二醇酯中的一种或多种。 具 体地, 所述亲水性生物大分子及水相、 油相、 乳化剂、 pH调节剂 等及其用量如上文中所描述。 发明的有益效果
本发明与现有技术相比, 具有以下优点及突出性效果: 3) At 4 - 37. Under the condition of C, the product of step 1) is added dropwise to the product of step 2), and stirring is continued at 200 - 800 rpm until a clear and clear homogeneous preparation is formed, and finally a hydrophilic biomacromolecular emulsion is obtained. Still another aspect of the present invention relates to the use of the hydrophilic biomacromer-containing emulsion of the present invention for the preparation of a medicament for treating or preventing diabetes, or lowering blood glucose, wherein the hydrophilic biomacromolecule is insulin or GLP- 1. Still another aspect of the present invention relates to the use of the hydrophilic biomacromolecular-containing emulsion of the present invention for the preparation of a medicament for treating or preventing osteoporosis, wherein the hydrophilic biomacromolecule is calcitonin or scorpion Parathyroid hormone, parathyroid hormone 1-84, or human parathyroid hormone 1-34. A further aspect of the invention relates to the use of an ester derivative of vitamin E and/or vitamin E for the preparation of a hydrophilic biomolecular-containing emulsion. Specifically, the hydrophilic biomacromer-containing emulsion is the hydrophilic biomacromolecular emulsion according to any one of the inventions. Specifically, the vitamin E is one or more selected from the group consisting of d-α-vitamin E and cU-a-vitamin E, and the ester derivative of the vitamin E is selected from the group consisting of da-vitamin E acetate. d a-vitamin E acetate, d-a-tocopheryl succinate, d-a-vitamin E succinate, d-a-vitamin E succinate, and d la-vitamin E amber One or more of acid polyethylene glycol esters. Specifically, the hydrophilic biomacromolecule and the aqueous phase, the oil phase, the emulsifier, the pH adjuster, and the like, and the amounts thereof are as described above. Advantageous effects of the invention Compared with the prior art, the invention has the following advantages and outstanding effects:
1 )本发明中,借助于维生素 E和 /或维生素 E的酯类衍生物, 实现亲水性生物大分子药物的口服化给药, 并且具有安全有效、 口服生物利用度高的特点,生物利用度可以达到 5 %、 10%、 12 %、 15 %甚至 30%以上; 1) In the present invention, oral administration of a hydrophilic biomacromolecular drug is achieved by means of an ester derivative of vitamin E and/or vitamin E, and is safe, effective, and has high oral bioavailability, and bioavailability. Degree can reach 5%, 10%, 12%, 15% or even 30%;
2 )制得的含亲水性生物低分子药物的维生素 E微乳剂 ,遇水 后能够自发乳化为 300nm以下的乳滴,更好的被胃肠道吸收利用, 发挥更好的生物活性。 2) The prepared vitamin E microemulsion containing a hydrophilic bio-low molecular drug can spontaneously emulsify into a droplet of 300 nm or less after being in contact with water, and is better absorbed and utilized by the gastrointestinal tract to exert better biological activity.
3 )本发明的制备工艺简单, 成本低廉, 适合于大规模工业化 生产。 附图说明 3) The preparation process of the invention is simple, low in cost and suitable for large-scale industrial production. DRAWINGS
Fig. 1: 不同给药方式下, 大鼠血糖变化图。 Fig. 1: Diagram of blood glucose changes in rats under different modes of administration.
Fig. 2: 不同给药方式下, 大鼠 PTH1-34血药浓度时相图。 具体实施方式 Fig. 2: Phase diagram of plasma concentration of rat PTH1-34 under different modes of administration. detailed description
下面将结合实施例对本发明的实施方案进行详细描述, 但是 本领域技术人员将会理解, 下列实施例仅用于说明本发明, 而不 应视为限定本发明的范围。 实施例中未注明具体条件者, 按照常 规条件或制造商建议的条件进行。 所用试剂或仪器未注明生产厂 商者, 均为可以通过市购获得的常规产品。 实施例 1 : 含鲑鱼降钙素的乳剂 (微乳剂) 的制备 The embodiments of the present invention are described in detail below with reference to the accompanying drawings. Those who do not specify the conditions in the examples are subject to the usual conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that are commercially available. Example 1 : Preparation of an emulsion containing salmon calcitonin (microemulsion)
其组成如下: Its composition is as follows:
鲑鱼降钙素 0. 001克 Salmon calcitonin 0. 001 g
1摩尔盐酸 适量
生理盐水 G.35克 1 mole of hydrochloric acid Saline G.35g
d-α-维生素 E 0.7克 油酸 Q.3克 聚乙二醇十二羟基硬脂酸酯(Solutol 1.5克 D-α-vitamin E 0.7 g oleic acid Q.3 g polyethylene glycol dodecyl stearate (Solutol 1.5 g
HS 15, BASF) HS 15, BASF)
吐温 80 1.5克。 Tween 80 1.5 grams.
该制剂的制备方法, 简述如下: The preparation method of the preparation is briefly described as follows:
1) 4。C下, 将鲑鱼降钙素溶于生理盐水, 加入适量盐酸、 搅 拌至澄清, 得 A溶液; 1) 4. C, the salmon calcitonin is dissolved in physiological saline, adding an appropriate amount of hydrochloric acid, stirring to clarify, to obtain a solution;
2) 70°C下, 将上述重量的 d-α-维生素 E、 油酸、 聚乙二醇 十二羟基硬脂酸酯、 吐温 80, 混合并在 200rpm搅拌条件下, 搅 拌至透明清亮; 2) at 70 ° C, the above weight of d-α-tocopherol, oleic acid, polyethylene glycol dodecyl stearate, Tween 80, mixed and stirred at 200 rpm, until transparent and clear;
3) 30。C下, 将 A 溶液, 逐滴加入到步骤 2) 的产物中, 在 800r/min转速下将混合物搅袢至透明清亮, 最终获得含鲑鱼降钙 素的乳剂 (微乳剂) (称为样品 1) 。 3) 30. Under C, add the A solution dropwise to the product of step 2), stir the mixture to a clear and clear at 800 r/min, and finally obtain an emulsion (microemulsion) containing salmon calcitonin (called sample 1). ).
本领域技术人员可以理解, 尽管实施例 1中的各组分的重量 单位是 g, 但是也可以理解为重量份, 即各组分之间满足上面的 实施例 1中的重量比例就可以。 实施例 2: 含重组人胰岛素的乳剂 (微乳剂) 的制备 It will be understood by those skilled in the art that although the weight unit of each component in Example 1 is g, it can be understood as a part by weight, i.e., the weight ratio in the above Example 1 is satisfied between the components. Example 2: Preparation of emulsion containing recombinant human insulin (microemulsion)
其组成如下: Its composition is as follows:
重组人胰岛素 0.04克 Recombinant human insulin 0.04 g
5摩尔氢氧化钠 适量 5 moles of sodium hydroxide
去离子水 1克 Deionized water 1 g
(il-a-维生素 E醋酸酯 1克 (il-a-vitamin E acetate 1 g
中链脂肪酸甘油酯( Labrafac Lipophile 0.5克
1349, Gattefosse) Medium chain fatty acid glyceride (Labrafac Lipophile 0.5g 1349, Gattefosse)
聚乙二醇辛酸 /癸酸甘油酯( Sofitgen® 3克 Polyethylene glycol octanoate / glyceryl citrate ( Sofitgen® 3 g
767, SAS0L) 767, SAS0L)
泊洛沙姆 188 (Lutrol F68, BASF) 0.2克 Poloxamer 188 (Lutrol F68, BASF) 0.2 g
大豆卵磷脂 (Epikuron 170, Degussa) 0.5克。 Soy lecithin (Epikuron 170, Degussa) 0.5 g.
该制剂的制备方法, 简述如下: The preparation method of the preparation is briefly described as follows:
1 )25°C下,将上述重量的重组人胰岛素溶于 0.5克去离子水, 加入适量氢氧化钠, 搅拌至澄清, 得 A溶液; 1) at 25 ° C, the above weight of recombinant human insulin is dissolved in 0.5 grams of deionized water, adding an appropriate amount of sodium hydroxide, stirred until clear, to obtain a solution;
2) 20。C下, 将上述重量的(Π-α-维生素 E醋酸酯、 中链脂肪 酸甘油酯、 聚乙二醇辛酸 /癸酸甘油酯、 泊洛沙姆 188、 大豆卵磷 脂, 和剩余水相混合, 并在 800rpm搅袢条件下搅拌至透明清亮; 2) 20. C, the above weight (Π-α-vitamin E acetate, medium chain fatty acid glyceride, polyethylene glycol caprylic/capric glyceride, poloxamer 188, soy lecithin, and the remaining aqueous phase are mixed, And stirred at 800 rpm to achieve clear and clear;
3) 4°C下,将 A溶液,逐滴加入到步驟 2 )的产物中,在 200r/min 转速下将混合物搅拌至透明清亮, 最终获得含重组人胰岛素的乳 剂 (微乳剂) (称为样品 2) 。 3) Add the A solution dropwise to the product of step 2) at 4 ° C, stir the mixture to clear and clear at 200 r / min, and finally obtain an emulsion (microemulsion) containing recombinant human insulin (called Sample 2).
本领域技术人员可以理解, 尽管实施例 2中的各组分的重量 单位是 g, 但是也可以理解为重量份, 即各组分之间满足上面的 实施例 2中的重量比例就可以。 实施例 3: 含 GLP-1的乳剂 (微乳剂) 的制备 It will be understood by those skilled in the art that although the weight unit of each component in Example 2 is g, it can be understood as a part by weight, i.e., the weight ratio in the above Example 2 is satisfied between the components. Example 3: Preparation of an emulsion containing GLP-1 (microemulsion)
其组成如下: Its composition is as follows:
GLP-1 0.0005克 GLP-1 0.0005 g
PBS緩冲液 0.3克 PBS buffer 0.3 g
d-α-维生素 E琥珀酸聚乙二醇酯( TPGS, 1.5克 d-α-Vitamin E succinic acid polyethylene glycol ester (TPGS, 1.5 g
Eastman ) Eastman )
聚乙二醇十二羟基硬脂酸酯(Solutol HS 2克 Polyethylene glycol dodecyl stearate (Solutol HS 2 g
15, BASF)
吐温 20 0.5克。 15, BASF) Tween 20 0.5 g.
该制剂的制备方法, 简述如下: The preparation method of the preparation is briefly described as follows:
1 ) 20°C下, 将上述重量的 GLP- 1溶于 PBS緩冲液, 搅拌至澄 清, 得 A溶液; 1) Dissolve the above weight of GLP-1 in PBS buffer at 20 ° C, stir until clarified to obtain A solution;
2) 60°C下, 将上述重量的 d-α-维生素 E琥珀酸聚乙二醇酯、 聚乙二醇十二羟基硬脂酸酯、 吐温 20, 混合并在 600rpm条件下 搅拌至透明清亮; 2) Mix the above weight of d-α-tocopheryl succinate, polyethylene glycol dodecyl stearate, and Tween 20 at 60 ° C, and mix at 600 rpm until transparent Clear
3) 37°C下, 将 A 溶液, 逐滴加入到步骤 2) 的产物中, 在 500r/min条件下将混合物搅拌至透明清亮, 最终获得含 GLP-1的 乳剂 (微乳剂) (称为样品 3) 。 3) Add the A solution dropwise to the product of step 2) at 37 ° C, stir the mixture to clear and clear at 500 r / min, and finally obtain a GLP-1 -containing emulsion (microemulsion) (called Sample 3).
本领域技术人员可以理解, 尽管实施例 3中的各组分的重量 单位是 g, 但是也可以理解为重量份, 即各组分之间满足上面的 实施例 3中的重量比例就可以。 实施例 4: 含 PTH 1-34的乳剂 (微乳剂) 的制备 It will be understood by those skilled in the art that although the weight unit of each component in Example 3 is g, it can be understood as a part by weight, i.e., the weight ratio in the above Example 3 is satisfied between the components. Example 4: Preparation of an emulsion containing PTH 1-34 (microemulsion)
其组成如下: Its composition is as follows:
PTH 1-34 0.01克 双蒸水 0.5克 PTH 1-34 0.01 g double distilled water 0.5 g
醋酸 适量 Acetic acid
d卜 α-维生素 E 0.7克 d Bu α-Vitamin E 0.7 g
d-α-维生素 Ε琥珀酸聚乙二醇酯(TPGS, 0.5克 D-α-vitamin succinic acid polyethylene glycol ester (TPGS, 0.5 g
Eastman ) Eastman )
大豆油 1.2克 Soybean oil 1.2 g
大豆卵磷脂 (Epikuron 170, Degussa) 0· 7克 Soy lecithin (Epikuron 170, Degussa) 0·7 g
聚氧乙烯醚(40)氢化蓖麻油(Cremophor 3克 Polyoxyethylene ether (40) hydrogenated castor oil (Cremophor 3 g
®RH 40, BASF)
聚乙二醇 400 2克。 ®RH 40, BASF) 2 g of polyethylene glycol 400.
该制剂的制备方法, 简述如下: The preparation method of the preparation is briefly described as follows:
1 ) 20。C下, 将上述重量的 PTH 1-34溶于双蒸水中, 加入适 量醋酸, 液搅拌至澄清, 得 A溶液; 1) 20. In C, the above weight of PTH 1-34 is dissolved in double distilled water, an appropriate amount of acetic acid is added, and the solution is stirred until clarified to obtain a solution A;
2 ) 50'C下, 将上述重量的(Π-α-维生素 E、 d-α-维生素 E琥 珀酸聚乙二醇酯、 大豆油、 大豆卵磷脂、 聚氧乙烯醚(40)氢化蓖 麻油、 聚乙二醇 400, 混合并在 400rpm条件下搅拌至透明清亮; 2) at 50'C, the above weight (Π-α-vitamin E, d-α-tocopheryl succinate, ethylene glycol ester, soybean oil, soy lecithin, polyoxyethylene ether (40) hydrogenated castor oil , polyethylene glycol 400, mixed and stirred at 400 rpm until clear and clear;
3) 30°C下, 将 A溶液, 逐滴加入到步骤 2 ) 的产物中, 并在 500r/min 转速下, 继续搅拌至透明清亮, 最终获得含 PTH 1-34 的乳剂 (微乳剂) (称为样品 4 ) 。 3) Add the A solution dropwise to the product of step 2) at 30 ° C, and continue stirring at 500 r / min to clear and clear, and finally obtain a PTH 1-34 containing emulsion (microemulsion) ( Called sample 4).
本领域技术人员可以理解, 尽管实施例 4中的各组分的重量 单位是 g, 但是也可以理解为重量份, 即各组分之间满足上面的 实施例 4中的重量比例就可以。 实施例 5: 含低分子量肝素的乳剂 (微乳剂) 的制备 It will be understood by those skilled in the art that although the weight unit of each component in Example 4 is g, it can be understood as a part by weight, i.e., the weight ratio in the above Example 4 is satisfied between the components. Example 5: Preparation of emulsion containing low molecular weight heparin (microemulsion)
其组成如下: Its composition is as follows:
低分子量肝素 0.3克 Low molecular weight heparin 0.3g
PBS緩冲液 0.5克 PBS buffer 0.5 g
dl-a-维生素 E 0.2克 Dl-a-vitamin E 0.2 g
聚甘油 -3-油酸酯 1.2克 Polyglycerol-3-oleate 1.2 g
吐温 80 1克 Tween 80 1 gram
聚乙二醇辛酸 /癸酸甘油酯 2.7克 Polyethylene glycol octanoate / glyceryl citrate 2.7 g
聚乙二醇 400 0.5克。 Polyethylene glycol 400 0.5 g.
该制剂的制备方法, 简述如下: The preparation method of the preparation is briefly described as follows:
1 ) 10°C下, 将上述重量的低分子量肝素溶于 PBS溶液, 搅袢 至澄清, 得 A溶液;
2 ) 50°C下, 将上述重量的 d卜 α-维生素 Ε、 聚甘油 -3-油酸 酯、 吐温 80、 聚乙二醇辛酸 /癸酸甘油酯、 聚乙二醇 400, 混合并 在 400rpm条件下搅拌至透明清亮; 1) at 10 ° C, the above weight of low molecular weight heparin is dissolved in PBS solution, stirred until clear, to obtain A solution; 2) mixing the above-mentioned weights of d-α-vitamin, polyglycerol-3-oleate, Tween 80, polyethylene glycol caprylic/capric glyceride, and polyethylene glycol 400 at 50 ° C Stir at 400 rpm until clear and clear;
3 ) 30°C下, 将 A溶液, 逐滴加入到步骤 2 ) 的产物中, 并在 500r/min转速下, 继续搅拌至透明清亮, 最终获得含低分子量肝 素的乳剂 (微乳剂) (称为样品 5 ) 。 3) Add the A solution dropwise to the product of step 2) at 30 ° C, and continue stirring at 500 r / min to clear and clear, and finally obtain an emulsion (microemulsion) containing low molecular weight heparin. For sample 5).
本领域技术人员可以理解, 尽管实施例 5中的各组分的重量 单位是 g, 但是也可以理解为重量份, 即各组分之间满足上面的 实施例 5中的重量比例就可以。 实施例 6: 含小分子干扰 RNA的乳剂 (微乳剂) 的制备 其组成如下: It will be understood by those skilled in the art that although the weight unit of each component in Example 5 is g, it can be understood as a part by weight, i.e., the weight ratio in the above Example 5 is satisfied between the components. Example 6: Preparation of an emulsion containing small interfering RNA (microemulsion) The composition is as follows:
小分子干扰 RNA (自制, 来源于乙肝病 0. 0003克 毒 P区, 500bp ) Small interfering RNA (self-made, from hepatitis B disease 0. 0003 g poison P area, 500bp)
注射用水 0. 5克 Water for injection 0. 5 grams
dl-α-维生素 E 0. 2克 聚甘油 -3-油酸酯 0. 3克 聚乙二醇辛酸 /癸酸甘油酯 2. 7克 甘油 0. 5克。 Dg-α-vitamin E 0. 2 g Polyglycerol-3-oleate 0. 3 g Polyethylene glycol octanoic acid / glyceryl citrate 2. 7 g Glycerol 0. 5 g.
该制剂的制备方法, 简述如下: The preparation method of the preparation is briefly described as follows:
1 ) 4 °C下, 将上述重量的小分子干扰 RNA溶解于注射用水, 搅拌至澄清, 得 A溶液; 1) Dissolving the above-mentioned small interfering RNA in water for injection at 4 ° C, stirring until clarification, to obtain A solution;
2 ) 50°C下, 将上述重量的 (U- a-维生素 E、 聚甘油 -3-油酸 酯、 聚乙二醇辛酸 /癸酸甘油酯、 甘油, 混合并在 300rpm条件下 搅拌至透明清亮; 2) Mix the above weight (U-a-vitamin E, polyglycerol-3-oleate, polyethylene glycol caprylic/capric glyceride, glycerin) at 50 ° C and stir until transparent at 300 rpm Clear
3 ) 10。C下, 将 A溶液, 逐滴加入到步骤 2 ) 的产物中, 并在
200r/min转速下, 继续搅拌至透明清亮, 最终获得含小分子千扰 RNA的乳剂 (微乳剂) (称为样品 6 ) 。 3) 10. C, the A solution is added dropwise to the product of step 2), and At 200 r/min, stirring was continued until clear and clear, and finally an emulsion (microemulsion) containing small molecule interference RNA (referred to as sample 6) was obtained.
本领域技术人员可以理解, 尽管实施例 6中的各组分的重量 单位是 g, 但是也可以理解为重量份, 即各组分之间满足上面的 实施例 6中的重量比例就可以。 实施例 7: 粒径测定试验 It will be understood by those skilled in the art that although the weight unit of each component in Example 6 is g, it can be understood as a part by weight, i.e., the weight ratio in the above Example 6 is satisfied between the components. Example 7: Particle size measurement test
用 Malvern Zetasizer 3000HSA粒度分析仪检测实施例 1-6 制备的样品 1-6的粒径, 测定前,样品用 Millipore超纯水稀释 30倍, 结果如表 1所示。 The particle size of Samples 1-6 prepared in Examples 1-6 was measured with a Malvern Zetasizer 3000HSA Particle Size Analyzer, and the sample was diluted 30 times with Millipore Ultrapure Water before the measurement. The results are shown in Table 1.
表 1: 样品 1-6稀释后的平均粒径 Table 1: Samples 1-6 Average particle size after dilution
实施例 8: 含重组人胰岛素的乳剂 (微乳剂) 的药效试验 口服试验组: 180 - 220克范围的雄性 SD大鼠 6只, 药物(试 验药物) 为实施例 2所制备的样品 2。 Example 8: Efficacy test of emulsion containing recombinant human insulin (microemulsion) Oral test group: 6 male SD rats in the range of 180 - 220 g, drug (test drug) was sample 2 prepared in Example 2.
口服对照组: 180 - 220克范围的雄性 SD大鼠 6只, 药物(对 照药物)按实施例 2的组成和操作步骤制备, 除了不添加 d卜 α- 维生素 Ε醋酸酯。
注射对照组: 180 - 220克范围的雄性 SD大鼠 6只, 药物为 胰岛素水溶液。 Oral control group: 6 male Sprague-Dawley rats in the range of 180-220 g, the drug (control drug) was prepared according to the composition and procedure of Example 2, except that no d-α-vitamin oxime acetate was added. Intravenous control group: 6 male Sprague-Dawley rats in the range of 180-220 g, the drug was an aqueous insulin solution.
试验方法: experiment method:
将体重为 180 - 220克范围的雄性 SD大鼠禁食 12h后开始试 验。 试验组为口服给药, 剂量按胰岛素计为 0. ½g/kg。 试验组大 鼠, 试验前用剂量为 50rag的戊巴比妥钠对大鼠进行麻醉后,按仰 位方式将其捆绑, 并在腹部切一小口, 用给药器对回肠给药, 给 药后, 缝合切口。 对照组为皮下注射对照药物, 给药剂量按胰岛 素计为 0. 04mg/kg。 Male Sprague-Dawley rats weighing 180-220 g were fasted for 12 h before starting the test. The test group was administered orally, and the dose was 0.11⁄2 g/kg in terms of insulin. Rats in the experimental group were anesthetized with sodium pentobarbital at a dose of 50 rag before the test, then bundled in the supine position, and cut into a small mouth in the abdomen, and administered to the ileum by the applicator. After that, suture the incision. The control group was administered subcutaneously as a control drug, and the dose was 0.04 mg/kg based on the insulin.
三组组均在给药后 0. 5、 1、 2、 3、 4h时刻点, 由尾静脉取血, 使用罗氏血糖测定仪测定血糖并计算每组内 6只大鼠的平均血糖 值, 结果如由图 1所示。 由图 1可见, 口服给药的试验组相对于 注射给药的对照组的生物利用度为 12. 5%。 实施例 9 : 含 PTH1-34的乳剂 (微乳剂) 生物利用度试验 试验组: 180 - 220克范围的雄性 SD大鼠 10只, 药物(试验 药物) 为实施例 4所制备的样品 4。 The three groups were all taken from the tail vein at the time of 0.5, 1, 2, 3, and 4 h after administration. The blood glucose was measured using a Roche blood glucose meter and the average blood glucose level of 6 rats in each group was calculated. As shown in Figure 1. As can be seen from Fig. 1, the bioavailability of the test group administered orally was 12.5% relative to the control group administered by injection. Example 9: Emulsion containing PTH1-34 (microemulsion) Bioavailability test Test group: 10 male SD rats in the range of 180 - 220 g, and the drug (test drug) was the sample prepared in Example 4.
对照组: 180 - 220 克范围的雄性 SD 大鼠 10 只, 药物为 PTH1-34水溶液, 采取注射给药。 Control group: 10 male SD rats in the range of 180-220 g, the drug was PTH1-34 aqueous solution, and administered by injection.
试验方法: experiment method:
将体重为 180 - 220克范围的雄性 SD大鼠禁食 12h后开始试 验。 试验组口服给药, 剂量按 PTH1-34计为 10(^g/kg。 口服组动 物, 实验前用剂量为 50mg的戊巴比妥钠对动物进行麻醉后,按仰 位方式将其捆绑, 并在腹部切一小口, 用给药器对回肠给药, 给 药后,缝合切口。对照组为皮下注射 PTH1- 34,给药剂量按 PTH1-34 计为 10 g/kg。
两组均在给药后 15、 30、 45、 60、 75、 90、 105min的时刻点, 由尾静脉取血,分离出血清备测。血清中 PTH 1-34浓度用 PTH 1-34 高灵敏度 EIA试剂盒检测。 结果如图 2所示, 其中 PTH1- 34血药 浓度曲线下面积计。 由图 2可见, 口服给药的试验组相对于注射 给药的对照组的生物利用度为 23. 13%。 Male SD rats weighing 180-220 g were fasted for 12 h before starting the test. The test group was orally administered, and the dose was 10 (^g/kg) according to PTH1-34. The animals in the oral group were anesthetized with sodium pentobarbital at a dose of 50 mg before the experiment, and then tied in an upright manner. A small opening was made in the abdomen, and the ileum was administered by the applicator. After the administration, the incision was sutured. The control group was subcutaneously injected with PTH1-34, and the dose was 10 g/kg as PTH1-34. The blood was taken from the tail vein at the time points of 15, 30, 45, 60, 75, 90, and 105 minutes after administration, and the serum was separated for testing. Serum PTH 1-34 concentrations were measured using the PTH 1-34 high sensitivity EIA kit. The results are shown in Figure 2, where the area under the PTH1-3 blood concentration curve is calculated. 2%。 The bioavailability of the test group administered orally was 23.13%.
尽管本发明的具体实施方式已经得到详细的描述, 本领域技 术人员将会理解。 根据已经公开的所有教导, 可以对那些细节进 行各种修改和替换, 这些改变均在本发明的保护范围之内。 本发 明的全部范围由所附权利要求及其任何等同物给出。
Although specific embodiments of the invention have been described in detail, those skilled in the art will understand. Various modifications and substitutions may be made to those details in light of the teachings of the invention, which are within the scope of the invention. The full scope of the invention is indicated by the appended claims and any equivalents thereof.
Claims
1. 一种含亲水性生物大分子的乳剂, 包含亲水性生物大分 子、 水相、 油相、 乳化剂, 其特征在于, 所述乳剂还包含维生素 E和 /或维生素 E的酯类衍生物。 An emulsion containing a hydrophilic biomacromolecule comprising a hydrophilic biomacromolecule, an aqueous phase, an oil phase, an emulsifier, characterized in that the emulsion further comprises an ester of vitamin E and/or vitamin E derivative.
2. 根据权利要求 1所述的乳剂, 其中, 所述亲水性生物大分 子选自蛋白质或多肽、 多糖、 以及核酸。 The emulsion according to claim 1, wherein the hydrophilic biomacyon is selected from the group consisting of a protein or a polypeptide, a polysaccharide, and a nucleic acid.
3. 根据权利要求 1 所述的乳剂, 其中, 所述维生素 E为选自 d- α -维生素 E和 dl- ct -维生素 E中的一种或多种, 所述维生素 E 的酯类衍生物为选自 d- α -维生素 E醋酸酯、 (U- α -维生素 Ε醋酸 酯、 d- α -维生素 E琥珀酸酯、 dl- α -维生素 Ε琥珀酸酯、 d- α -维 生素 E琥珀酸聚乙二醇酯、和 dl- a -维生素 E琥珀酸聚乙二醇酯中 的一种或多种。 The emulsion according to claim 1, wherein the vitamin E is one or more selected from the group consisting of d-α-vitamin E and dl-ct-vitamin E, and the ester derivative of the vitamin E It is selected from d-α-vitamin E acetate, (U-α-vitamin oxime acetate, d-α-tocopheryl succinate, dl-α-vitamin succinate, d-α-vitamin E succinic acid One or more of polyethylene glycol ester, and dl-a-tocopheryl succinate polyethylene glycol ester.
4. 根据权利要求 1所述的乳剂, 其中, 所述亲水性生物大分子 为 0. 01 - 1重量份, 并且所述维生素 E和 /或维生素 E的酯类衍生 物为 50 - 1000重量份、 5 Q - 5 GG重量份、 或者 100 - 3GG重量份。 The emulsion according to claim 1 , wherein the hydrophilic biomacromolecule is 0.01 to 1 part by weight, and the ester derivative of the vitamin E and/or vitamin E is 50 to 1000 weight. Parts, 5 Q - 5 GG parts by weight, or 100 - 3 GG parts by weight.
5. 根据权利要求 4所述的乳剂, 其中, 所述水相、 油相、 以 及乳化剂合计为 20 - 2000重量份、20 - 1000重量份、或者 50 -500 重量份。 The emulsion according to claim 4, wherein the aqueous phase, the oil phase, and the emulsifier are 20 - 2000 parts by weight, 20 - 1000 parts by weight, or 50 - 500 parts by weight in total.
6. 根据权利要求 1所述的乳剂, 其中, 所述蛋白质或多肽选 自降钙素、 胰岛素、 GLP-1、 甲状旁腺激素、 和生长激素; 所述多 糖选自肝素、 低分子肝素、 硫酸软骨素、 硫酸角质素、 和透明质 酸; 所述核酸选自反义核酸、 核酶、 干扰 RNA、 DECOY核酸、 和三 链核酸; 具体地; 所述降钙素为鲑鱼降钙素、 鰻鱼降钙素、 或人 降钙素; 所述胰岛素为猪胰岛素、 牛胰岛素、 或人胰岛素; 所述 甲状旁腺激素为人体甲状旁腺激素 1-84、 或人甲状旁腺激素 1-34、 所述生长激素为猪生长激素、 牛生长激素、 或人生长激素 bThe emulsion according to claim 1, wherein the protein or polypeptide is selected from the group consisting of calcitonin, insulin, GLP-1, parathyroid hormone, and growth hormone; the polysaccharide is selected from the group consisting of heparin, low molecular weight heparin, Chondroitin sulfate, keratan sulfate, and hyaluronic acid; the nucleic acid is selected from the group consisting of an antisense nucleic acid, a ribozyme, an interfering RNA, a DECOY nucleic acid, and a triple-stranded nucleic acid; specifically; the calcitonin is salmon calcitonin, Salmon calcitonin, or human calcitonin; the insulin is porcine insulin, bovine insulin, or human insulin; the parathyroid hormone is human parathyroid hormone 1-84, or human parathyroid hormone 1-34, the growth hormone is porcine growth hormone, bovine growth hormone, or human growth hormone b
7. 根据权利要求 1所述的乳剂, 其满足如下的 ( 1 ) - ( 3 ) 项中的任一项或者多项: 7. The emulsion according to claim 1, which satisfies any one or more of the following (1) - (3):
( 1 )所述水相为选自水、 生理盐水、 以及水相緩沖液中的一种或 多种; (1) the aqueous phase is one or more selected from the group consisting of water, physiological saline, and an aqueous phase buffer;
( 2 )所述油相为选自中链脂肪酸甘油酯、 大豆油、 玉米油、 花生 油、 油酸、 聚乙二醇 400、 甘油、 乙醇、 以及丙二醇中的一种或 多种; (2) the oil phase is one or more selected from the group consisting of medium chain fatty acid glycerides, soybean oil, corn oil, peanut oil, oleic acid, polyethylene glycol 400, glycerin, ethanol, and propylene glycol;
( 3 )所述乳化剂为选自大豆卵磷脂、蛋黄卵磷脂、 泊洛沙姆 188、 泊洛沙姆 407、 卡波姆、 吐温 20、 吐温 80、 聚乙二醇十二羟基硬 脂酸酯、 聚氧乙烯醚(35)蓖麻油、 聚氧乙烯醚(40)氢化蓖麻油、 聚甘油 -6-二油酸酯、 聚甘油 -3-油酸酯、 聚乙二醇 -32-月桂酸甘 油酯、聚乙二醇- 32-硬脂酸甘油酯、 以及聚乙二醇辛酸 /癸酸甘油 酯中的一种或多种。 (3) The emulsifier is selected from the group consisting of soybean lecithin, egg yolk lecithin, poloxamer 188, poloxamer 407, carbomer, Tween 20, Tween 80, polyethylene glycol dodecyl hard Fatty acid ester, polyoxyethylene ether (35) castor oil, polyoxyethylene ether (40) hydrogenated castor oil, polyglycerol-6-dioleate, polyglycerol-3-oleate, polyethylene glycol-32 One or more of glyceryl laurate, polyethylene glycol-32-stearate, and polyethylene glycol caprylic/capric glyceride.
8. 根据权利要求 1 所述的乳剂, 其还包含 pH调节剂, 所述 pH值调节剂选自盐酸、 乳酸、 醋酸、 枸橼酸、 磷酸、 氢氧化钠、 碳酸钠、 碳酸氢钠、 磷酸氢二钠、 以及磷酸二氢钠中的一种或多 种。 8. The emulsion according to claim 1, further comprising a pH adjusting agent selected from the group consisting of hydrochloric acid, lactic acid, acetic acid, citric acid, phosphoric acid, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, phosphoric acid One or more of disodium hydrogenate and sodium dihydrogen phosphate.
9. 根据权利要求 1至 8中任一项所迷的乳剂, 其为微乳剂。 9. An emulsion according to any one of claims 1 to 8 which is a microemulsion.
10. 根据权利要求 1所述的乳剂, 其组分及含量如下: 重组人胰岛素 0. 03 - 0. 05重量份 氢氧化钠 适量 The emulsion according to claim 1, wherein the composition and content are as follows: recombinant human insulin 0. 03 - 0. 05 parts by weight sodium hydroxide
去离子水 0. 8 - 1. 2重量份 dl- α -维生素 E醋酸酯 0. 8 - 1. 2重量份 中链脂肪酸甘油酯 0. 6 - 0. 7重量份 聚乙二醇辛酸 /癸酸甘油酯 2. 5 - 3. 5重量份 泊洛沙姆 188 0.1 - 0.3重量份 大豆卵磷脂 0.4- 0.6重量份; 具体地, 所述乳剂的组分及含量如下 Desicfied water 0. 8 - 1. 2 parts by weight of dl-α-vitamin E acetate 0. 8 - 1. 2 parts by weight of medium chain fatty acid glyceride 0. 6 - 0. 7 parts by weight of polyethylene glycol octanoic acid / hydrazine Acid glyceride 2. 5 - 3. 5 parts by weight Poloxamer 188 0.1 - 0.3 parts by weight of soybean lecithin 0.4 - 0.6 parts by weight; specifically, the components and contents of the emulsion are as follows
重组人胰岛素 0.04重量份 氢氧化钠 适量 Recombinant human insulin 0.04 parts by weight sodium hydroxide
去离子水 1重量份 Deionized water 1 part by weight
dl-α -维生素 E醋酸酯 1重量份 Dl-α-vitamin E acetate 1 part by weight
中链脂肪酸甘油酯 0.5重量份 聚乙二醇辛酸 /癸酸甘油酯 3重量份 Medium chain fatty acid glyceride 0.5 parts by weight Polyethylene glycol octanoate / glyceryl citrate 3 parts by weight
泊洛沙姆 188 Polosham 188
大豆卵磷脂 Soy lecithin
11. 根据权利要求 1所述的乳剂, 11. The emulsion of claim 1
PTH 1-34 PTH 1-34
水 Water
醋酸 适量 Acetic acid
dl-α -维生素 E 0.6 - 0. 8重量份 d-α -维生素 E琥珀酸聚乙二醇酯 0.4- 0. 6重量份 大豆油 1.0- 1. 4重量份 大豆卵磷脂 0.6 - 0. 8重量份 聚氧乙烯醚(40)氢化蓖麻油 2.5- 3. 5重量份 聚乙二醇 400 1.5 - 2. 5重量份; 具体地, 所述乳剂的组分及含量如下 Dl-α -Vitamin E 0.6 - 0. 8 parts by weight of d-α-vitamin E succinic acid polyethylene glycol ester 0.4- 0. 6 parts by weight of soybean oil 1.0 - 1. 4 parts by weight of soy lecithin 0.6 - 0. 8 Parts by weight of polyoxyethylene ether (40) hydrogenated castor oil 2.5 - 3. 5 parts by weight of polyethylene glycol 400 1.5 - 2. 5 parts by weight; specifically, the components and contents of the emulsion are as follows
PTH 1-34 0.01重量份 水 0.5重量份 PTH 1-34 0.01 parts by weight water 0.5 parts by weight
醋酸 适量 Acetic acid
dl-a -维生素 E 0.7重量份 d- α -维生素 E琥珀酸聚乙二醇酯 0. 5重量份 Dl-a - vitamin E 0.7 parts by weight 5重量份。 D-α-Vitamin E succinate polyethylene glycol ester 0. 5 parts by weight
大豆油 1. 2重量份 Soybean oil 1. 2 parts by weight
大豆卵磷脂 0. 7重量份 Soy lecithin 0. 7 parts by weight
聚氧乙烯醚(40)氢化蓖麻油 3重量份 Polyoxyethylene ether (40) hydrogenated castor oil 3 parts by weight
聚乙二醇 400 2重量份。 Polyethylene glycol 400 2 parts by weight.
12. 权利要求 1至 11中任一项所述的含亲水性生物大分子的 乳剂的制备方法, 包括下述步骤: The method for preparing a hydrophilic biomacromer-containing emulsion according to any one of claims 1 to 11, comprising the steps of:
1 ) 在 4 - 25。C条件下, 将亲水性生物大分子溶于水相; 1) At 4-25. Under the condition of C, the hydrophilic biological macromolecule is dissolved in the aqueous phase;
2 )在 20 - 70 °C条件下, 将维生素 E和 /或维生素 E的酯类衍生物 与油相、乳化剂相混合, 并在 200 - 800rnip搅拌条件下持续搅拌, 直至整个体系呈透明清亮状; 2) Mix the ester derivatives of vitamin E and/or vitamin E with the oil phase and emulsifier at 20 - 70 °C, and continue stirring under the stirring condition of 200 - 800rnip until the whole system is transparent and clear. Shape
3 )在 4 - 37。C条件下, 将步驟 1 )产物, 逐滴加入步骤 2 ) 产物 中, 并在 200 - 800rmp条件下继续搅拌, 直至形成透明清亮的均 匀制剂, 最终获得含亲水性生物大分子的乳剂。 3) At 4 - 37. Under the condition of C, the product of step 1) is added dropwise to the product of step 2), and stirring is continued at 200 - 800 rpm until a clear and clear homogeneous preparation is formed, and finally a hydrophilic biomacromolecular emulsion is obtained.
13. 权利要求 10所述的乳剂在制备治疗或预防糖尿病、 或者 降低血糖的药物中的用途。 13. Use of an emulsion according to claim 10 for the manufacture of a medicament for the treatment or prevention of diabetes, or for lowering blood glucose.
14. 权利要求 11所述的乳剂在制备治疗或预防骨质疏松的药 物中的用途。 14. Use of an emulsion according to claim 11 for the manufacture of a medicament for the treatment or prevention of osteoporosis.
15. 维生素 E和 /或维生素 E的酯类衍生物在制备含亲水性生 物大分子的乳剂中的用途。 15. Use of an ester derivative of vitamin E and/or vitamin E in the preparation of a emulsion containing a hydrophilic biomolecule.
16. 一种治疗或预防糖尿病、 或者降低血糖的方法, 包括给 予有效量的权利要求 10所述的乳剂的步骤。 16. A method of treating or preventing diabetes, or lowering blood glucose, comprising the step of administering an effective amount of the emulsion of claim 10.
17. 一种治疗或预防骨质疏松的方法, 包括给予有效量的权 利要求 11所述的乳剂的步骤。 17. A method of treating or preventing osteoporosis comprising the step of administering an effective amount of the emulsion of claim 11.
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