CN102125520A - 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
- CN102125520A CN102125520A CN2011100444263A CN201110044426A CN102125520A CN 102125520 A CN102125520 A CN 102125520A CN 2011100444263 A CN2011100444263 A CN 2011100444263A CN 201110044426 A CN201110044426 A CN 201110044426A CN 102125520 A CN102125520 A CN 102125520A
- Authority
- CN
- China
- Prior art keywords
- weight portion
- emulsion
- alpha
- tocopherol
- vitamin
- 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.)
- Pending
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- 239000000839 emulsion Substances 0.000 title claims abstract description 83
- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- 229920002521 macromolecule Polymers 0.000 title abstract 3
- 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 109
- 229930003427 Vitamin E Natural products 0.000 claims abstract description 36
- 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 36
- 229940046009 vitamin E Drugs 0.000 claims abstract description 36
- 235000019165 vitamin E Nutrition 0.000 claims abstract description 36
- 239000011709 vitamin E Substances 0.000 claims abstract description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 12
- -1 ester derivatives of vitamin E Chemical class 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims description 34
- 229960000984 tocofersolan Drugs 0.000 claims description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 22
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 21
- 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 21
- 239000004530 micro-emulsion Substances 0.000 claims description 19
- 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
- 239000002076 α-tocopherol Substances 0.000 claims description 18
- 235000004835 α-tocopherol Nutrition 0.000 claims description 18
- 239000003921 oil Substances 0.000 claims description 16
- 235000019198 oils Nutrition 0.000 claims description 16
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 claims description 15
- 239000011627 DL-alpha-tocopherol Substances 0.000 claims description 15
- 235000001815 DL-alpha-tocopherol Nutrition 0.000 claims description 15
- 229950007687 macrogol ester Drugs 0.000 claims description 15
- 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 claims description 14
- 239000002202 Polyethylene glycol Substances 0.000 claims description 14
- 229960003773 calcitonin (salmon synthetic) Drugs 0.000 claims description 14
- 125000005456 glyceride group Chemical group 0.000 claims description 14
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 14
- 229920001223 polyethylene glycol Polymers 0.000 claims description 14
- 108010068072 salmon calcitonin Proteins 0.000 claims description 14
- 229940083466 soybean lecithin Drugs 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- 210000004369 blood Anatomy 0.000 claims description 13
- 239000008280 blood Substances 0.000 claims description 13
- 229940042585 tocopherol acetate Drugs 0.000 claims description 13
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 claims description 12
- 239000001384 succinic acid Substances 0.000 claims description 12
- 102000004877 Insulin Human genes 0.000 claims description 11
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 11
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 11
- 239000000194 fatty acid Substances 0.000 claims description 11
- 229930195729 fatty acid Natural products 0.000 claims description 11
- 150000004665 fatty acids Chemical class 0.000 claims description 11
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims description 11
- 108090001061 Insulin Proteins 0.000 claims description 10
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 10
- 239000012071 phase Substances 0.000 claims description 10
- 229940051841 polyoxyethylene ether Drugs 0.000 claims description 10
- 229920000056 polyoxyethylene ether Polymers 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
- 239000011626 DL-alpha-tocopherylacetate Substances 0.000 claims description 9
- 235000001809 DL-alpha-tocopherylacetate Nutrition 0.000 claims description 9
- 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 9
- 102400000322 Glucagon-like peptide 1 Human genes 0.000 claims description 9
- 101000976075 Homo sapiens Insulin Proteins 0.000 claims description 9
- 108090000445 Parathyroid hormone Proteins 0.000 claims description 9
- 229940125396 insulin Drugs 0.000 claims description 9
- 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 9
- 108020004707 nucleic acids Proteins 0.000 claims description 9
- 102000039446 nucleic acids Human genes 0.000 claims description 9
- 150000007523 nucleic acids Chemical class 0.000 claims description 9
- 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 9
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 102000003982 Parathyroid hormone Human genes 0.000 claims description 8
- 239000004359 castor oil Substances 0.000 claims description 8
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 8
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- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 8
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- IELOKBJPULMYRW-IKTKBOKFSA-N 4-oxo-4-[[(2S)-2,5,7,8-tetramethyl-2-[(4S,8S)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-yl]oxy]butanoic acid Chemical compound CC(C)CCC[C@H](C)CCC[C@H](C)CCC[C@@](C)(CC1)Oc(c(C)c2C)c1c(C)c2OC(CCC(O)=O)=O IELOKBJPULMYRW-IKTKBOKFSA-N 0.000 claims description 6
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Abstract
The invention relates to an emulsion containing a hydrophilic biological macromolecule, a preparation method and application thereof, belonging to the fields of pharmacology and pharmaceutics. In particular, the emulsion contains a hydrophilic biological macromolecule, a water phase, an oil phase and an emulsifying agent. The emulsion is characterized by also comprising vitamin E and/or ester derivatives of vitamin E. The emulsion has the characteristic of high oral bioavailability and is safe and effective.
Description
Technical field
The invention belongs to materia medica and galenic pharmacy field, relate to a kind of Emulsion, Preparation Method And The Use that contains the hydrophilic biomacromolecule.
Background technology
Insulin is the hydrophilic biopharmaceutical macromolecular drug of representative, comprising protein or polypeptide, polysaccharide, nucleic acid, be a class medicine that becomes more and more important in the drug world, but a common feature of this class material is, oral administration is invalid, needs frequent drug administration by injection in clinical.Therefore, developing the drug delivery system of a kind of patient's degree of complying with height, suitable oral administration, is the common ideal of the world of medicine.
In decades, research worker adopts strategies such as covalent modification, enzyme inhibitor, absorption enhancer, microcapsules and microsphere parcel, W/O (Water-In-Oil) Emulsion, in the hope of solving the low problem of these hydrophilic biopharmaceutical macromolecular drug oral administration biaavailabilities.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；RogerR.C.New，et?al(1997)Adv.Drug.Del?iver.Rev.25：59-69；AnjaGraf，et?al(2008)Int.J.Pharm.350：351-360；R.NeslihanGursoy?et?al(2004)Biomed.Pharmacother.58：173-182；CN01115327.X，US4849405，US5824638。
But the potential safety hazard of the solution hydrophilic substance oral administration method of above-mentioned routine, for example: covalent modification can reduce pharmaceutically active, and may change pharmacology, the toxicity of drug molecule, brings serious potential safety hazard; The enzyme inhibitor is taken enlargement or the hypertrophy of digesting and assimilating disorder even pancreas with causing for a long time; Absorption enhancer might cell membrane cause irreversible destruction, takes for a long time to cause membrane poisoning.
In addition, the data of having reported at present about the oral administration biaavailability of biomacromolecule are unsatisfactory.Oral insulin microemulsion bioavailability only is 4.44% (Amani Elsayed, et al, European Journal of Pharmaceutics and Biopharmaceutics73 (2009) 269-279); Oral PTH preparation bioavailability only is 2.1% (AndreaLeone-Bay, et al, Pharmaceutical Research, Vol.18, No.7,2001).
Vitamin E claims tocopherol again, is a kind of common fatsoluble vitamin E.When using as antioxidant, concentration is generally less than 1%.Vitamin E also often is used as supplementary, is widely used in fields such as health care, food, medical treatment, beauty treatment.Vitamin E is because of its special structure, to some hydrophobic molecules such as paclitaxel, ciclosporin, steroidal class materials, good dissolubility is arranged, people such as Constantinides in view of the above, outside " water-soluble ", " oil is molten ", the notion (Constantinides, P.P., et al. (2004) Adv DrugDeliv Rev.56:175-82) of " vitamin E is molten " has been proposed again.
With the vitamin E is solvent, is applied to the novel drug administration carrier of hydrophobic molecule, sees people's such as Y.Kato research at first, Xiang Guan research subsequently emerge in an endless stream (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, and 540; US 6,458, and 373; US7030155B2).
Vitamin E has the safety of height as food source property material and supplementary, but present research is not seen the report that utilizes vitamin E to realize the oralization administration of hydrophilic biopharmaceutical macromolecular drug as yet only with the carrier of vitamin E as dewatering medicament.
Summary of the invention
The inventor has obtained a kind of Emulsion that contains the hydrophilic biomacromolecule through a large amount of tests and creatively work, wherein, uses the carrier of the esters derivative of vitamin E or vitamin E as the hydrophilic biomacromolecule.Vitamin E or its esters derivative itself are nontoxic, can effectively solve the security hidden trouble of the hydrophilic biopharmaceutical macromolecular drug of present oral administration.The inventor is surprised to find, and with the esters derivative of vitamin E or the vitamin E drug administration carrier as the hydrophilic biomacromolecule, can significantly improve the oral administration biaavailability of these hydrophilic biopharmaceutical macromolecular drugs.
Following invention is provided thus:
A kind of Emulsion that contains the hydrophilic biomacromolecule comprises hydrophilic biomacromolecule, water, oil phase, emulsifying agent, it is characterized in that, described Emulsion also comprises the esters derivative of vitamin E and/or vitamin E.
According to each described Emulsion of the present invention, wherein, described hydrophilic biomacromolecule is selected from protein or polypeptide, polysaccharide and nucleic acid.Described hydrophilic biomacromolecule can separate acquisition from living organism, also can obtain by genetic engineering means or organic synthesis mode.
According to each described Emulsion of the present invention, wherein, described vitamin E is to be selected from d-alpha-tocopherol and the dl-alpha-tocopherol one or more, and the esters derivative of described vitamin E is to be selected from d-alpha-tocopherol acetate, dl-alpha-tocopherol acetate, d-alpha-tocopherol succinate, dl-alpha-tocopherol succinate, d-alpha-tocopherol succinic acid macrogol ester and the dl-alpha-tocopherol succinic acid macrogol ester one or more.
The vitamin E among the present invention or the esters derivative of vitamin E can be natural, also can be synthetic.
According to each described Emulsion of the present invention, wherein, described hydrophilic biomacromolecule is the 0.01-1 weight portion, and the esters derivative of described vitamin E and/or vitamin E is 50-1000 weight portion, 50-500 weight portion or 100-300 weight portion.
According to each described Emulsion of the present invention, wherein, described water, oil phase and emulsifying agent add up to 20-2000 weight portion, 20-1000 weight portion or 50-500 weight portion.To those skilled in the art, can easily determine water, oil phase and emulsifying agent amount separately.
According to each described Emulsion of the present invention, wherein, described protein or polypeptide are selected from calcitonin, insulin, GLP-1 (glucagon-like-peptide-1), parathyroid hormone and growth hormone; Described polysaccharide is selected from heparin, low molecular weight heparin (mean molecule quantity is at 4000-6000), chondroitin sulfate, keratan sulfate and hyaluronic acid; Described nucleic acid is selected from antisensenucleic acids, ribozyme, RNA interfering, DECOY nucleic acid and three chain nucleic acid; Particularly; Described calcitonin is salmon calcitonin see calcimar, Anguillar japonica calcitonin or human calcitonin; Described insulin is Iletin II (Lilly), bovine insulin or insulin human; Described parathyroid hormone is that human body parathyroid hormone 1-84 or human parathyroid hormone 1-34, described growth hormone are pig growth hormone, bovine growth hormone or human growth hormone.
According to each described Emulsion of the present invention, wherein, described water is to be selected from water, normal saline and the water buffer one or more.
According to each described Emulsion of the present invention, wherein, described emulsifying agent is for being selected from soybean lecithin, Ovum Gallus domesticus Flavus lecithin, poloxamer 188, poloxamer 407, carbomer, polysorbas20, Tween 80, polyethyleneglycol-12-hydroxy stearin, polyoxyethylene ether (35) Oleum Ricini, polyoxyethylene ether (40) castor oil hydrogenated, polyglycereol-6-dioleate, polyglycereol-3-oleate, Polyethylene Glycol-32-glyceryl laurate ester, Polyethylene Glycol-32-tristerin and the Polyethylene Glycol caprylic/capric glyceride one or more.
According to each described Emulsion of the present invention, wherein, described oil phase is to be selected from medium chain length fatty acid triglyceride, soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, oleic acid, PEG400, glycerol, ethanol and the propylene glycol one or more.Described medium chain length fatty acid triglyceride can be in medium-chain fatty acid monoglyceride, medium-chain fatty acid diglyceride and the MCT Oil one or more.Medium-chain fatty acid in the described medium chain length fatty acid triglyceride can be combined in any one or a plurality of hydroxy position in the glycerol molecule, when forming medium-chain fatty acid diglyceride or MCT Oil, bonded medium-chain fatty acid molecule can be identical or different on the hydroxyl in the glycerol molecule.In the present invention, medium-chain fatty acid is meant the fatty acid of carbon number 6-12, and it can be saturated, also can be undersaturated, can be straight chain, also can be side chain.Particularly, described medium-chain fatty acid is sad and/or capric acid.
According to each described Emulsion of the present invention, it also comprises the pH regulator agent, and described pH value regulator is selected from one or more in hydrochloric acid, lactic acid, acetic acid, citric acid, phosphoric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydrogen phosphate and the sodium dihydrogen phosphate.
According to each described Emulsion of the present invention, it is a microemulsion.Microemulsion is meant by water, oil, emulsifying agent to be formed, isotropism, transparent, thermodynamically stable dispersion, and particle diameter is less than 500nm usually.
According to each described Emulsion of the present invention, it passes through oral administration.
In a specific embodiment of the present invention, the component and the content of the described Emulsion that contains the hydrophilic biomacromolecule are as follows:
Salmon calcitonin see calcimar 0.001 weight portion
1 mole hydrochloride is an amount of
Normal saline 0.35 weight portion
D-alpha-tocopherol 0.7 weight portion
Oleic acid 0.3 weight portion
Polyethyleneglycol-12-hydroxy stearin 1.5 weight portions
Tween 80 1.5 weight portions.
The invention still further relates to the purposes of this Emulsion in the medicine of preparation treatment or prevention of osteoporosis.The invention still further relates to the method for a kind of treatment or prevention of osteoporosis, comprise the step of this Emulsion that gives effective dose.
In one embodiment of the invention, the component and the content of the described Emulsion that contains the hydrophilic biomacromolecule are as follows:
Recombinant human insulin 0.03-0.05 weight portion
Sodium hydroxide is an amount of
Deionized water 0.8-1.2 weight portion
Dl-alpha-tocopherol acetate 0.8-1.2 weight portion
(for example Labrafac 0.6-0.7 weight portion Lipophile 1349, Gattefosse) for medium chain length fatty acid triglyceride
Polyethylene Glycol caprylic/capric glyceride (2.5-3.5 weight portion for example
767, SASOL)
Poloxamer 188 0.1-0.3 weight portions
Soybean lecithin 0.4-0.6 weight portion.
The invention still further relates to the purposes of this Emulsion in the medicine of preparation treatment or prevent diabetes or blood sugar lowering.The invention still further relates to the method for a kind of treatment or prevent diabetes or blood sugar lowering, comprise the step of this Emulsion that gives effective dose.In a specific embodiment of the present invention, the component and the content of the described Emulsion that contains the hydrophilic biomacromolecule are as follows:
Recombinant human insulin's 0.04 weight portion
Sodium hydroxide is an amount of
Deionized water 1 weight portion
Dl-alpha-tocopherol acetate 1 weight portion
Medium chain length fatty acid triglyceride (Labrafac 0.5 weight portion Lipophile 1349 for example, Gattefosse)
Polyethylene Glycol caprylic/capric glyceride (3 weight portions for example
767, SASOL)
Poloxamer 188 0.2 weight portions
Soybean lecithin 0.5 weight portion.
The invention still further relates to the purposes of this Emulsion in the medicine of preparation treatment or prevent diabetes or blood sugar lowering.
In a specific embodiment of the present invention, the component and the content of the described Emulsion that contains the hydrophilic biomacromolecule are as follows:
GLP-1 0.0005 weight portion
PBS buffer 0.3 weight portion
D-alpha-tocopherol succinic acid macrogol ester 1.5 weight portions
Polyethyleneglycol-12-hydroxy stearin 2 weight portions
Polysorbas20 0.5 weight portion.
The invention still further relates to the purposes of this Emulsion in the medicine of preparation treatment or prevent diabetes or blood sugar lowering.The invention still further relates to the method for a kind of treatment or prevent diabetes or blood sugar lowering, comprise the step of this Emulsion that gives effective dose.
In one embodiment of the invention, the component and the content of the described Emulsion that contains the hydrophilic biomacromolecule are as follows:
PTH 1-34 0.005-0.015 weight portion
Water (preferred distilled water) 0.4-0.6 weight portion
Acetic acid is an amount of
Dl-alpha-tocopherol 0.6-0.8 weight portion
D-alpha-tocopherol succinic acid macrogol ester 0.4-0.6 weight portion
Soybean oil 1.0-1.4 weight portion
Soybean lecithin 0.6-0.8 weight portion
Polyoxyethylene ether (40) castor oil hydrogenated 2.5-3.5 weight portion
PEG400 1.5-2.5 weight portion.
The invention still further relates to the purposes of this Emulsion in the medicine of preparation treatment or prevention of osteoporosis.The invention still further relates to the method for a kind of treatment or prevention of osteoporosis, comprise the step of this Emulsion that gives effective dose.
In a specific embodiment of the present invention, the component and the content of the described Emulsion that contains the hydrophilic biomacromolecule are as follows:
PTH 1-34 0.01 weight portion
Water (preferred distilled water) 0.5 weight portion
Acetic acid is an amount of
Dl-alpha-tocopherol 0.7 weight portion
D-alpha-tocopherol succinic acid macrogol ester 0.5 weight portion
Soybean oil 1.2 weight portions
Soybean lecithin 0.7 weight portion
Polyoxyethylene ether (40) castor oil hydrogenated 3 weight portions
PEG400 2 weight portions.
The invention still further relates to the purposes of this Emulsion in the medicine of preparation treatment or prevention of osteoporosis.
In a specific embodiment of the present invention, the component and the content of the described Emulsion that contains the hydrophilic biomacromolecule are as follows:
Low molecular weight heparin 0.3 weight portion
PBS buffer 0.5 weight portion
Dl-alpha-tocopherol 0.2 weight portion
Polyglycereol-3-oleate 1.2 weight portions
Tween 80 1 weight portion
Polyethylene Glycol caprylic/capric glyceride 2.7 weight portions
PEG400 0.5 weight portion.
The invention still further relates to this Emulsion the preparation anticoagulation and or the medicine of thrombolytic in purposes.The invention still further relates to a kind of treatment or pre-preventing thrombosis or anticoagulant method, comprise the step of this Emulsion that gives effective dose.
In a specific embodiment of the present invention, the component and the content of the described Emulsion that contains the hydrophilic biomacromolecule are as follows:
Small molecules interference RNA (for example size is 500bp) 0.0003 weight portion
Water for injection 0.5 weight portion
Dl-alpha-tocopherol 0.2 weight portion
Polyglycereol-3-oleate 0.3 weight portion
Polyethylene Glycol caprylic/capric glyceride 2.7 weight portions
Glycerol 0.5 weight portion.
Another aspect of the present invention relates to each described preparation method that contains the Emulsion of hydrophilic biomacromolecule of the present invention, comprises the steps:
1) under 4-25 ℃ of condition, the hydrophilic biomacromolecule is soluble in the aqueous phase;
2) under 20-70 ℃ of condition, esters derivative and oil phase, the emulsifying agent of vitamin E and/or vitamin E mixed mutually, and under the 200-800rmp stirring condition, continue to stir, be the transparent clear shape until whole system;
3) under 4-37 ℃ of condition,, dropwise add step 2 with the step 1) product) in the product, and under the 200-800rmp condition, continue to stir, until the even preparation that forms transparent clear, the final Emulsion that obtains to contain the hydrophilic biomacromolecule.
The purposes of the Emulsion that contains the hydrophilic biomacromolecule of the present invention in the medicine of preparation treatment or prevent diabetes or blood sugar lowering that also relate in one aspect to of the present invention, wherein, described hydrophilic biomacromolecule is insulin or GLP-1.
The purposes of the Emulsion that contains the hydrophilic biomacromolecule of the present invention in the medicine of preparation treatment or prevention of osteoporosis that also relate in one aspect to of the present invention, wherein, described hydrophilic biomacromolecule is calcitonin, parathyroid hormone, parathyroid hormone 1-84 or human parathyroid hormone 1-34.
The esters derivative that also relates in one aspect to vitamin E and/or vitamin E of the present invention contains purposes in the Emulsion of hydrophilic biomacromolecule in preparation.Particularly, the described Emulsion that contains the hydrophilic biomacromolecule is each described Emulsion that contains the hydrophilic biomacromolecule of the present invention.Particularly, described vitamin E is to be selected from d-alpha-tocopherol and the dl-alpha-tocopherol one or more, and the esters derivative of described vitamin E is to be selected from d-alpha-tocopherol acetate, dl-alpha-tocopherol acetate, d-alpha-tocopherol succinate, dl-alpha-tocopherol succinate, d-alpha-tocopherol succinic acid macrogol ester and the dl-alpha-tocopherol succinic acid macrogol ester one or more.Particularly, described hydrophilic biomacromolecule and water, oil phase, emulsifying agent, pH regulator agent etc. and consumption thereof as mentioned described in.
The beneficial effect of the invention
The present invention compared with prior art has the following advantages and the salience effect:
1) among the present invention, esters derivative by means of vitamin E and/or vitamin E, realize the oralization administration of hydrophilic biopharmaceutical macromolecular drug, and have the characteristics safe and effective, that oral administration biaavailability is high, bioavailability can reach more than 5%, 10%, 12%, 15% even 30%;
2) the vitamin E microemulsion that contains the biological low-molecule drug of hydrophilic that makes can spontaneous emulsification be the following emulsion droplet of 300nm behind the chance water, is better utilized by gastrointestinal absorption, brings into play better biological activity.
3) preparation technology of the present invention is simple, and is with low cost, is suitable for large-scale industrial production.
Description of drawings
Fig. 1: under the different modes of administration, the rat blood sugar variation diagram.
Fig. 2: under the different modes of administration, phasor during P of Rats TH1-34 concentration.
The specific embodiment
Below in conjunction with embodiment embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example only is used to illustrate the present invention, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person among the embodiment carries out according to the condition of normal condition or manufacturer's suggestion.The unreceipted person of production firm of agents useful for same or instrument, being can be by the conventional products of commercial acquisition.
Embodiment 1: contain the preparation of the Emulsion (microemulsion) of salmon calcitonin see calcimar
It is composed as follows:
Salmon calcitonin see calcimar 0.001 gram
1 mole hydrochloride is an amount of
Normal saline 0.35 gram
D-alpha-tocopherol 0.7 gram
Oleic acid 0.3 gram
Polyethyleneglycol-12-hydroxy stearin (Solutol 1.5 gram HS 15, BASF)
Tween 80 1.5 grams.
The preparation method of said preparation is summarized as follows:
1) under 4 ℃, salmon calcitonin see calcimar is dissolved in normal saline, adds appropriate hydrochloric acid, stirs to clarify, A solution;
2) under 70 ℃,, mix being incorporated under the 200rpm stirring condition, be stirred to transparent clear d-alpha-tocopherol, oleic acid, polyethyleneglycol-12-hydroxy stearin, the Tween 80 of above-mentioned weight;
3) under 30 ℃,, dropwise join step 2 with A solution) product in, under the 800r/min rotating speed, mixture is stirred to transparent clear, the final Emulsion (microemulsion) (being called sample 1) that obtains to contain salmon calcitonin see calcimar.
Although it will be understood by those skilled in the art that the unit of weight of each component among the embodiment 1 is g, also can be understood as weight portion, the part by weight among the embodiment 1 above promptly satisfying between each component just can.
Embodiment 2: contain the preparation of recombinant human insulin's Emulsion (microemulsion)
It is composed as follows:
Recombinant human insulin's 0.04 gram
5 molar sodium hydroxides are an amount of
Deionized water 1 gram
Dl-alpha-tocopherol acetate 1 gram
Medium chain length fatty acid triglyceride (Labrafac Lipophile 0.5 gram 1349, Gattefosse)
Polyethylene Glycol caprylic/capric glyceride (
3 grams 767, SASOL)
Poloxamer 188 (Lutrol F68, BASF) 0.2 gram
(Epikuron 170, Degussa) 0.5 gram for soybean lecithin.
The preparation method of said preparation is summarized as follows:
1) under 25 ℃, the recombinant human insulin of above-mentioned weight is dissolved in 0.5 gram deionized water, adds an amount of sodium hydroxide, stir to clarify, A solution;
2) under 20 ℃, dl-alpha-tocopherol acetate, medium chain length fatty acid triglyceride, Polyethylene Glycol caprylic/capric glyceride, poloxamer 188, soybean lecithin with above-mentioned weight, mix with the residue water, and under the 800rpm stirring condition, be stirred to transparent clear;
3) under 4 ℃,, dropwise join step 2 with A solution) product in, under the 200r/min rotating speed, mixture is stirred to transparent clear, the final Emulsion (microemulsion) (being called sample 2) that obtains to contain the recombinant human insulin.
Although it will be understood by those skilled in the art that the unit of weight of each component among the embodiment 2 is g, also can be understood as weight portion, the part by weight among the embodiment 2 above promptly satisfying between each component just can.
Embodiment 3: contain the preparation of the Emulsion (microemulsion) of GLP-1
It is composed as follows:
GLP-1 0.0005 gram
PBS buffer 0.3 gram
D-alpha-tocopherol succinic acid macrogol ester (TPGS, 1.5 gram Eastman)
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 2 grams 15, BASF)
Polysorbas20 0.5 gram.
The preparation method of said preparation is summarized as follows:
1) under 20 ℃, the GLP-1 of above-mentioned weight is dissolved in the PBS buffer, stirs to clarify, A solution;
2) under 60 ℃,, mix to be incorporated under the 600rpm condition being stirred to transparent clear with d-alpha-tocopherol succinic acid macrogol ester, polyethyleneglycol-12-hydroxy stearin, the polysorbas20 of above-mentioned weight;
3) under 37 ℃,, dropwise join step 2 with A solution) product in, under the 500r/min condition, mixture is stirred to transparent clear, the final Emulsion (microemulsion) (being called sample 3) that obtains to contain GLP-1.
Although it will be understood by those skilled in the art that the unit of weight of each component among the embodiment 3 is g, also can be understood as weight portion, the part by weight among the embodiment 3 above promptly satisfying between each component just can.
Embodiment 4: contain the preparation of the Emulsion (microemulsion) of PTH 1-34
It is composed as follows:
PTH 1-34 0.01 gram
Distilled water 0.5 gram
Acetic acid is an amount of
Dl-alpha-tocopherol 0.7 gram
D-alpha-tocopherol succinic acid macrogol ester (TPGS, 0.5 gram Eastman)
Soybean oil 1.2 grams
(Epikuron 170, Degussa) 0.7 gram for soybean lecithin
Polyoxyethylene ether (40) castor oil hydrogenated (Cremophor 3 grams
40, BASF)
PEG400 2 grams.
The preparation method of said preparation is summarized as follows:
1) under 20 ℃, the PTH 1-34 of above-mentioned weight is dissolved in the distilled water, adds an amount of acetic acid, liquid stirs to clarify, A solution;
2) under 50 ℃, with dl-alpha-tocopherol, d-alpha-tocopherol succinic acid macrogol ester, soybean oil, soybean lecithin, polyoxyethylene ether (40) castor oil hydrogenated, the PEG400 of above-mentioned weight, mix to be incorporated under the 400rpm condition being stirred to transparent clear;
3) under 30 ℃,, dropwise join step 2 with A solution) product in, and under the 500r/min rotating speed, continue to be stirred to transparent clear, the final Emulsion (microemulsion) (being called sample 4) that obtains to contain PTH 1-34.
Although it will be understood by those skilled in the art that the unit of weight of each component among the embodiment 4 is g, also can be understood as weight portion, the part by weight among the embodiment 4 above promptly satisfying between each component just can.
Embodiment 5: contain the preparation of the Emulsion (microemulsion) of low molecular weight heparin
It is composed as follows:
Low molecular weight heparin 0.3 gram
PBS buffer 0.5 gram
Dl-alpha-tocopherol 0.2 gram
Polyglycereol-3-oleate 1.2 grams
Tween 80 1 gram
Polyethylene Glycol caprylic/capric glyceride 2.7 grams
PEG400 0.5 gram.
The preparation method of said preparation is summarized as follows:
1) under 10 ℃, the low molecular weight heparin of above-mentioned weight is dissolved in PBS solution, stirs to clarify, A solution;
2) under 50 ℃,, mix to be incorporated under the 400rpm condition being stirred to transparent clear with dl-alpha-tocopherol, polyglycereol-3-oleate, Tween 80, Polyethylene Glycol caprylic/capric glyceride, the PEG400 of above-mentioned weight;
3) under 30 ℃,, dropwise join step 2 with A solution) product in, and under the 500r/min rotating speed, continue to be stirred to transparent clear, the final Emulsion (microemulsion) (being called sample 5) that obtains to contain low molecular weight heparin.
Although it will be understood by those skilled in the art that the unit of weight of each component among the embodiment 5 is g, also can be understood as weight portion, the part by weight among the embodiment 5 above promptly satisfying between each component just can.
Embodiment 6: contain the preparation of the Emulsion (microemulsion) of small molecules interference RNA
It is composed as follows:
(self-control derives from the malicious P of sick 0.0003 gram of hepatitis B district, 500bp) to small molecules interference RNA
Water for injection 0.5 gram
Dl-alpha-tocopherol 0.2 gram
Polyglycereol-3-oleate 0.3 gram
Polyethylene Glycol caprylic/capric glyceride 2.7 grams
Glycerol 0.5 gram.
The preparation method of said preparation is summarized as follows:
1) under 4 ℃, the small molecules interference RNA of above-mentioned weight is dissolved in water for injection, stirs to clarify, A solution;
2) under 50 ℃,, mix to be incorporated under the 300rpm condition being stirred to transparent clear with dl-alpha-tocopherol, polyglycereol-3-oleate, Polyethylene Glycol caprylic/capric glyceride, the glycerol of above-mentioned weight;
3) under 10 ℃,, dropwise join step 2 with A solution) product in, and under the 200r/min rotating speed, continue to be stirred to transparent clear, the final Emulsion (microemulsion) (being called sample 6) that obtains to contain small molecules interference RNA.
Although it will be understood by those skilled in the art that the unit of weight of each component among the embodiment 6 is g, also can be understood as weight portion, the part by weight among the embodiment 6 above promptly satisfying between each component just can.
Embodiment 7: the particle size determination test
Detect the particle diameter of the sample 1-6 of embodiment 1-6 preparation with Malvern Zetasizer 3000HSA Particle Size Analyzer, before the mensuration, sample is with 30 times of Millipore ultra-pure water dilutions, and the result is as shown in table 1.
Table 1: the mean diameter after the sample 1-6 dilution
| Sample number into spectrum | Particle diameter/nm |
| 1 | 170 |
| 2 | 68 |
| 3 | 267 |
| 4 | 235 |
| 5 | 182 |
| 6 | 280 |
Embodiment 8: the test of pesticide effectiveness that contains recombinant human insulin's Emulsion (microemulsion)
6 of the male SD rats of oral test group: 180-220 gram scope, medicine (trial drug) are the prepared sample 2 of embodiment 2.
6 of the male SD rats of oral matched group: 180-220 gram scope, medicine (control drug) are pressed composition and the operating procedure preparation of embodiment 2, except not adding d1-alpha-tocopherol acetate.
6 of the male SD rats of injection matched group: 180-220 gram scope, medicine is an insulin solution.
Test method:
Be to begin test behind the male SD rat fasting 12h of 180-220 gram scope with body weight.Test group is an oral administration, and dosage is counted 0.4mg/kg by insulin.Rats in test groups is after the pentobarbital sodium of 50mg is anaesthetized rat, by facing upward a mode it to be bundled, and cut an osculum at abdominal part with dosage before the test,,, sews up the incision after the administration to the ileum administration with administrator.Matched group is the subcutaneous injection control drug, and dosage is counted 0.04mg/kg by insulin.
Three groups of groups all after administration 0.5,1,2,3, the 4h moment point, get blood by the tail vein, use Luo Shi blood sugar detection instrument to measure blood glucose and calculate every group in the average blood sugar values of 6 rats, the result is as by shown in Figure 1.As seen from Figure 1, the test group of oral administration is 12.5% with respect to the bioavailability of the matched group of drug administration by injection.
Embodiment 9: contain Emulsion (microemulsion) the bioavailability test of PTH1-34
10 of the male SD rats of test group: 180-220 gram scope, medicine (trial drug) are the prepared sample 4 of embodiment 4.
10 of the male SD rats of matched group: 180-220 gram scope, medicine is the PTH1-34 aqueous solution, takes drug administration by injection.
Test method:
Be to begin test behind the male SD rat fasting 12h of 180-220 gram scope with body weight.The test group oral administration, dosage is counted 100 μ g/kg by PTH1-34.Oral treated animal is after the pentobarbital sodium of 50mg is anaesthetized animal, by facing upward a mode it to be bundled, and cut an osculum at abdominal part with dosage before the experiment,,, sews up the incision after the administration to the ileum administration with administrator.Matched group is subcutaneous injection PTH1-34, and dosage is counted 10 μ g/kg by PTH1-34.
Two groups all after administration 15,30,45,60,75,90, the moment point of 105min, get blood by the tail vein, isolate serum and be equipped with and survey.PTH1-34 concentration detects with PTH1-34 high sensitivity EIA test kit in the serum.The result as shown in Figure 2, areameter under the PTH1-34 plasma concentration curve wherein.As seen from Figure 2, the test group of oral administration is 23.13% with respect to the bioavailability of the matched group of drug administration by injection.
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various modifications and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.
Claims (15)
1. an Emulsion that contains the hydrophilic biomacromolecule comprises hydrophilic biomacromolecule, water, oil phase, emulsifying agent, it is characterized in that, described Emulsion also comprises the esters derivative of vitamin E and/or vitamin E.
2. Emulsion according to claim 1, wherein, described hydrophilic biomacromolecule is selected from protein or polypeptide, polysaccharide and nucleic acid.
3. Emulsion according to claim 1, wherein, described vitamin E is to be selected from d-alpha-tocopherol and the dl-alpha-tocopherol one or more, and the esters derivative of described vitamin E is to be selected from d-alpha-tocopherol acetate, dl-alpha-tocopherol acetate, d-alpha-tocopherol succinate, dl-alpha-tocopherol succinate, d-alpha-tocopherol succinic acid macrogol ester and the dl-alpha-tocopherol succinic acid macrogol ester one or more.
4. Emulsion according to claim 1, wherein, described hydrophilic biomacromolecule is the 0.01-1 weight portion, and the esters derivative of described vitamin E and/or vitamin E is 50-1000 weight portion, 50-500 weight portion or 100-300 weight portion.
5. Emulsion according to claim 4, wherein, described water, oil phase and emulsifying agent add up to 20-2000 weight portion, 20-1000 weight portion or 50-500 weight portion.
6. Emulsion according to claim 1, wherein, described protein or polypeptide are selected from calcitonin, insulin, GLP-1, parathyroid hormone and growth hormone; Described polysaccharide is selected from heparin, Low molecular heparin, chondroitin sulfate, keratan sulfate and hyaluronic acid; Described nucleic acid is selected from antisensenucleic acids, ribozyme, RNA interfering, DECOY nucleic acid and three chain nucleic acid; Particularly; Described calcitonin is salmon calcitonin see calcimar, Anguillar japonica calcitonin or human calcitonin; Described insulin is Iletin II (Lilly), bovine insulin or insulin human; Described parathyroid hormone is that human body parathyroid hormone 1-84 or human parathyroid hormone 1-34, described growth hormone are pig growth hormone, bovine growth hormone or human growth hormone.
7. Emulsion according to claim 1, its satisfy in following (1)-(3) each or multinomial:
(1) described water is to be selected from water, normal saline and the water buffer one or more;
(2) described oil phase is to be selected from medium chain length fatty acid triglyceride, soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, oleic acid, PEG400, glycerol, ethanol and the propylene glycol one or more;
(3) described emulsifying agent is for being selected from soybean lecithin, Ovum Gallus domesticus Flavus lecithin, poloxamer 188, poloxamer 407, carbomer, polysorbas20, Tween 80, polyethyleneglycol-12-hydroxy stearin, polyoxyethylene ether (35) Oleum Ricini, polyoxyethylene ether (40) castor oil hydrogenated, polyglycereol-6-dioleate, polyglycereol-3-oleate, Polyethylene Glycol-32-glyceryl laurate ester, Polyethylene Glycol-32-tristerin, and in the Polyethylene Glycol caprylic/capric glyceride one or more.
8. Emulsion according to claim 1, it also comprises the pH regulator agent, and described pH value regulator is selected from one or more in hydrochloric acid, lactic acid, acetic acid, citric acid, phosphoric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydrogen phosphate and the sodium dihydrogen phosphate.
9. according to each described Emulsion in the claim 1 to 8, it is a microemulsion.
10. Emulsion according to claim 1, its component and content are as follows:
Recombinant human insulin 0.03-0.05 weight portion
Sodium hydroxide is an amount of
Deionized water 0.8-1.2 weight portion
Dl-alpha-tocopherol acetate 0.8-1.2 weight portion
Medium chain length fatty acid triglyceride 0.6-0.7 weight portion
Polyethylene Glycol caprylic/capric glyceride 2.5-3.5 weight portion
Poloxamer 188 0.1-0.3 weight portions
Soybean lecithin 0.4-0.6 weight portion;
Particularly, the component of described Emulsion and content are as follows:
Recombinant human insulin's 0.04 weight portion
Sodium hydroxide is an amount of
Deionized water 1 weight portion
Dl-alpha-tocopherol acetate 1 weight portion
Medium chain length fatty acid triglyceride 0.5 weight portion
Polyethylene Glycol caprylic/capric glyceride 3 weight portions
Poloxamer 188 0.2 weight portions
Soybean lecithin 0.5 weight portion.
11. Emulsion according to claim 1, its component and content are as follows:
PTH1-34 0.005-0.015 weight portion
Water 0.4-0.6 weight portion
Acetic acid is an amount of
Dl-alpha-tocopherol 0.6-0.8 weight portion
D-alpha-tocopherol succinic acid macrogol ester 0.4-0.6 weight portion
Soybean oil 1.0-1.4 weight portion
Soybean lecithin 0.6-0.8 weight portion
Polyoxyethylene ether (40) castor oil hydrogenated 2.5-3.5 weight portion
PEG400 1.5-2.5 weight portion;
Particularly, the component of described Emulsion and content are as follows:
PTH1-34 0.01 weight portion
Water 0.5 weight portion
Acetic acid is an amount of
Dl-alpha-tocopherol 0.7 weight portion
D-alpha-tocopherol succinic acid macrogol ester 0.5 weight portion
Soybean oil 1.2 weight portions
Soybean lecithin 0.7 weight portion
Polyoxyethylene ether (40) castor oil hydrogenated 3 weight portions
PEG400 2 weight portions.
12. each described preparation method that contains the Emulsion of hydrophilic biomacromolecule comprises the steps: in the claim 1 to 11
1) under 4-25 ℃ of condition, the hydrophilic biomacromolecule is soluble in the aqueous phase;
2) under 20-70 ℃ of condition, esters derivative and oil phase, the emulsifying agent of vitamin E and/or vitamin E mixed mutually, and under the 200-800rmp stirring condition, continue to stir, be the transparent clear shape until whole system;
3) under 4-37 ℃ of condition,, dropwise add step 2 with the step 1) product) in the product, and under the 200-800rmp condition, continue to stir, until the even preparation that forms transparent clear, the final Emulsion that obtains to contain the hydrophilic biomacromolecule.
13. the purposes of the described Emulsion of claim 10 in the medicine of preparation treatment or prevent diabetes or blood sugar lowering.
14. the purposes of the described Emulsion of claim 11 in the medicine of preparation treatment or prevention of osteoporosis.
15. the esters derivative of vitamin E and/or vitamin E contains purposes in the Emulsion of hydrophilic biomacromolecule in preparation.
Priority Applications (2)
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| CN2011100444263A CN102125520A (en) | 2011-02-24 | 2011-02-24 | Emulsion containing hydrophilic biological macromolecule, preparation method and application thereof |
| PCT/CN2011/000814 WO2012113116A1 (en) | 2011-02-24 | 2011-05-10 | Emulsion containing hydrophilic biological macromolecule, preparation method and application thereof |
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| CN2011100444263A CN102125520A (en) | 2011-02-24 | 2011-02-24 | Emulsion containing hydrophilic biological macromolecule, preparation method and application thereof |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103861090A (en) * | 2012-12-18 | 2014-06-18 | 美迪思生物科技(北京)有限公司 | Protein or peptide containing hydrophobic solution, preparation method and application thereof |
| CN104840415A (en) * | 2014-02-19 | 2015-08-19 | 香港浸会大学 | Long-acting controlled release liposome gel combination containing blood sugar reducing active component, and preparation method thereof |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1318416A (en) * | 2001-04-20 | 2001-10-24 | 清华大学 | Method of preparing oil-phase oral insulin preparation |
| CN1582143A (en) * | 2001-10-11 | 2005-02-16 | Imi生物医药公司 | Pro-micelle pharmaceutical compositions |
| CN1596889A (en) * | 2004-07-23 | 2005-03-23 | 沈阳药科大学 | Vitamin E emulsion and its freeze-dried emulsion compound and preparation method |
| CN1743000A (en) * | 2004-08-30 | 2006-03-08 | 上海医药工业研究院 | Parathyroid hormone transnosal preparation and preparing method |
| CN101422431A (en) * | 2007-12-28 | 2009-05-06 | 上海医药工业研究院 | Insulation administration preparation through nose |
| CN101428009A (en) * | 2008-04-09 | 2009-05-13 | 上海医药工业研究院 | Insulin intranasal inhalation powder spray |
| CN102113996A (en) * | 2011-02-24 | 2011-07-06 | 美迪思生物科技(北京)有限公司 | Oral formulations containing protein or peptide, and preparation method and application thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101076354B (en) * | 2004-08-03 | 2011-01-12 | 生命健康科学有限公司 | Carrier used for medicine giving for intestine |
| CN1839876A (en) * | 2006-01-18 | 2006-10-04 | 复旦大学 | Heparin oral nano composition and its preparation method |
| EP1867323A1 (en) * | 2006-06-13 | 2007-12-19 | Farmatron Ltd. | Pharmaceutical compositions with biological barriers permeation enhancing properties |
-
2011
- 2011-02-24 CN CN2011100444263A patent/CN102125520A/en active Pending
- 2011-05-10 WO PCT/CN2011/000814 patent/WO2012113116A1/en active Application Filing
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1318416A (en) * | 2001-04-20 | 2001-10-24 | 清华大学 | Method of preparing oil-phase oral insulin preparation |
| CN1582143A (en) * | 2001-10-11 | 2005-02-16 | Imi生物医药公司 | Pro-micelle pharmaceutical compositions |
| CN1596889A (en) * | 2004-07-23 | 2005-03-23 | 沈阳药科大学 | Vitamin E emulsion and its freeze-dried emulsion compound and preparation method |
| CN1743000A (en) * | 2004-08-30 | 2006-03-08 | 上海医药工业研究院 | Parathyroid hormone transnosal preparation and preparing method |
| CN101422431A (en) * | 2007-12-28 | 2009-05-06 | 上海医药工业研究院 | Insulation administration preparation through nose |
| CN101428009A (en) * | 2008-04-09 | 2009-05-13 | 上海医药工业研究院 | Insulin intranasal inhalation powder spray |
| CN102113996A (en) * | 2011-02-24 | 2011-07-06 | 美迪思生物科技(北京)有限公司 | Oral formulations containing protein or peptide, and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 《药用辅料手册》 20050131 R.C.罗，等 维生素E 31-34 , 1 * |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111345290A (en) * | 2012-03-05 | 2020-06-30 | 阿彻丹尼尔斯米德兰德公司 | Microemulsions and their use as delivery systems |
| CN103861090A (en) * | 2012-12-18 | 2014-06-18 | 美迪思生物科技(北京)有限公司 | Protein or peptide containing hydrophobic solution, preparation method and application thereof |
| CN104840415A (en) * | 2014-02-19 | 2015-08-19 | 香港浸会大学 | Long-acting controlled release liposome gel combination containing blood sugar reducing active component, and preparation method thereof |
| WO2015123997A1 (en) * | 2014-02-19 | 2015-08-27 | 香港浸会大学 | Long-acting gel composition comprising blood sugar reducing active component and capable of controlling and releasing liposome, and preparation method therefor |
| CN104840415B (en) * | 2014-02-19 | 2019-03-15 | 香港浸会大学 | Long-acting controlled release lipidosome gel composition containing blood-sugar decreasing active and preparation method thereof |
| CN110114061A (en) * | 2016-12-28 | 2019-08-09 | 小林制药株式会社 | Topical composition |
| CN108013475A (en) * | 2017-12-26 | 2018-05-11 | 华中农业大学 | A kind of polypeptide-polysaccharide composite lotion and preparation method thereof |
| CN108013475B (en) * | 2017-12-26 | 2021-06-08 | 华中农业大学 | Polypeptide-polysaccharide composite emulsion and preparation method thereof |
| CN114599388A (en) * | 2019-09-05 | 2022-06-07 | 株式会社艾跨Bnp | Oral pharmaceutical composition containing teriparatide and preparation method thereof |
| EP4026566A4 (en) * | 2019-09-05 | 2023-05-10 | Icure BNP Co., Ltd. | Oral pharmaceutical composition comprising teriparatide and method for preparing same |
| CN112220752A (en) * | 2020-10-21 | 2021-01-15 | 四川大学 | Micelle and preparation method and application thereof |
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|---|---|
| WO2012113116A1 (en) | 2012-08-30 |
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