CN103784400B - A kind of pegylated phospholipids contain the oral micellar preparation of insulin - Google Patents
A kind of pegylated phospholipids contain the oral micellar preparation of insulin Download PDFInfo
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- CN103784400B CN103784400B CN201210427544.7A CN201210427544A CN103784400B CN 103784400 B CN103784400 B CN 103784400B CN 201210427544 A CN201210427544 A CN 201210427544A CN 103784400 B CN103784400 B CN 103784400B
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- 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 title claims abstract description 140
- 102000004877 Insulin Human genes 0.000 title claims abstract description 70
- 108090001061 Insulin Proteins 0.000 title claims abstract description 70
- 229940125396 insulin Drugs 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 69
- 150000003904 phospholipids Chemical class 0.000 title claims abstract description 39
- 239000003814 drug Substances 0.000 claims abstract description 32
- 229940125395 oral insulin Drugs 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 6
- 230000002218 hypoglycaemic effect Effects 0.000 claims abstract description 5
- 239000002671 adjuvant Substances 0.000 claims abstract description 4
- 239000000693 micelle Substances 0.000 claims description 40
- 239000000243 solution Substances 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 230000006320 pegylation Effects 0.000 claims description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 239000011574 phosphorus Substances 0.000 claims description 2
- 239000002245 particle Substances 0.000 abstract description 11
- 229920001223 polyethylene glycol Polymers 0.000 abstract description 8
- 230000002209 hydrophobic effect Effects 0.000 abstract description 7
- 239000002202 Polyethylene glycol Substances 0.000 abstract description 5
- 108090000790 Enzymes Proteins 0.000 abstract description 3
- 102000004190 Enzymes Human genes 0.000 abstract description 3
- 210000004082 barrier epithelial cell Anatomy 0.000 abstract description 2
- 230000004890 epithelial barrier function Effects 0.000 abstract description 2
- 230000004224 protection Effects 0.000 abstract description 2
- 230000001681 protective effect Effects 0.000 abstract description 2
- 230000004888 barrier function Effects 0.000 abstract 2
- 230000017531 blood circulation Effects 0.000 abstract 1
- 239000008280 blood Substances 0.000 description 14
- 210000004369 blood Anatomy 0.000 description 14
- 229940079593 drug Drugs 0.000 description 12
- 235000019197 fats Nutrition 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 230000008901 benefit Effects 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 229920000642 polymer Polymers 0.000 description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 210000001015 abdomen Anatomy 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000000539 dimer Substances 0.000 description 3
- 239000012738 dissolution medium Substances 0.000 description 3
- 238000001647 drug administration Methods 0.000 description 3
- 238000005538 encapsulation Methods 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 239000008176 lyophilized powder Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 150000005846 sugar alcohols Polymers 0.000 description 3
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 2
- RYCNUMLMNKHWPZ-SNVBAGLBSA-N 1-acetyl-sn-glycero-3-phosphocholine Chemical compound CC(=O)OC[C@@H](O)COP([O-])(=O)OCC[N+](C)(C)C RYCNUMLMNKHWPZ-SNVBAGLBSA-N 0.000 description 2
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 2
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid ester group Chemical group C(CCCCCCCCCCC)(=O)O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 230000002183 duodenal effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000004153 islets of langerhan Anatomy 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- -1 mean diameter 15nm Substances 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 2
- 150000003905 phosphatidylinositols Chemical class 0.000 description 2
- 229920000151 polyglycol Polymers 0.000 description 2
- 239000010695 polyglycol Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- TWJNQYPJQDRXPH-UHFFFAOYSA-N 2-cyanobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1C#N TWJNQYPJQDRXPH-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- NKKPYEQGRMPARG-UHFFFAOYSA-N C(O)CN.[P] Chemical compound C(O)CN.[P] NKKPYEQGRMPARG-UHFFFAOYSA-N 0.000 description 1
- 206010018473 Glycosuria Diseases 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 235000021353 Lignoceric acid Nutrition 0.000 description 1
- CQXMAMUUWHYSIY-UHFFFAOYSA-N Lignoceric acid Natural products CCCCCCCCCCCCCCCCCCCCCCCC(=O)OCCC1=CC=C(O)C=C1 CQXMAMUUWHYSIY-UHFFFAOYSA-N 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 206010024604 Lipoatrophy Diseases 0.000 description 1
- 206010049287 Lipodystrophy acquired Diseases 0.000 description 1
- 235000021360 Myristic acid Nutrition 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 108010067035 Pancrelipase Proteins 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- FRKBLBQTSTUKOV-UHFFFAOYSA-N diphosphatidyl glycerol Natural products OP(O)(=O)OCC(OP(O)(O)=O)COP(O)(O)=O FRKBLBQTSTUKOV-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- FARYTWBWLZAXNK-WAYWQWQTSA-N ethyl (z)-3-(methylamino)but-2-enoate Chemical compound CCOC(=O)\C=C(\C)NC FARYTWBWLZAXNK-WAYWQWQTSA-N 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 101150032953 ins1 gene Proteins 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 235000020778 linoleic acid Nutrition 0.000 description 1
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 1
- 208000006132 lipodystrophy Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000004531 microgranule Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 230000003836 peripheral circulation Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 210000003240 portal vein Anatomy 0.000 description 1
- 239000011241 protective layer Substances 0.000 description 1
- 210000001187 pylorus Anatomy 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a kind of be available for oral insulin nano micellar preparation, it contains the insulin of therapeutically effective amount, pegylated phospholipids and pharmaceutically acceptable adjuvant.This insulin micellar preparation adopts a step self-assembling method preparation, can form the very uniform particle of particle diameter, to the envelop rate of insulin up to more than 99.0%.In this micellar preparation; the surface that polyethylene glycol long chain can be distributed in the hydrophobic core containing medicine forms hydrophilic protective films; be conducive to overcoming and in gi system, there is rete malpighii barrier, enzyme barrier and epithelial barrier, protection insulin smoothly enters blood circulation and plays hypoglycemic activity.
Description
Technical field
The invention belongs to field of medicaments, it is related to a kind of be available for oral insulin micellar preparation and preparation method thereof.
Background technology
Insulin (Insulin, INS), due to its unique blood sugar lowering curative effect, is insulin-dependent glycosuria so far
The drug of first choice of patient.At present, almost all of insulin preparation all passes through drug administration by injection.This not only brings very big to patient
Financial burden, have impact on the quality of life of patient and its family members, and frequent long term injections medication simultaneously also can produce many bad anti-
Ying Ru：Insulin edema, hypoglycemic reaction, hypertrophy lipodystrophy and lipoatrophy etc..
Oral administration is a kind of most common administering mode, is be easiest in numerous route of administration be accepted by patients one
Kind, for needing the patient of long-term or frequent medication especially for those, this administering mode of drug oral is in compliance
Aspect is significantly better than other administration route.The oral administration route of insulin can simulate physiological insulin secretion, rebuilds physiology
The ratio of portal vein insulin concentration and peripheral circulation insulin concentration approximate 1: 5 under state, therefore, oral delivery systems are pancreases
Island optimal Non-parenteral Delivery Routes of element, it is to avoid injection pain and inconvenience, the compliance of patient is strong.Oral insulin conveys
System key issue to be solved is to improve its bioavailability so as to reach effective blood drug level.
Medicine carrying system of polymer micelle is more and more to be subject to the advantages of its stable in properties, biocompatibility and lyotropy
Concern, be a study hotspot of pharmaceutical field in recent years.At present, the research of polymer micelle preparation is mostly focused on injection
Administration.Micellar preparation particle diameter is little, stable in properties, preparation method simple, and has the advantages that protective effect to the medicine that it contains,
People begin one's study it as the carrier of oral administration.Polymer micelle is developed and contributes to reducing medicine for oral administration system
To gastrointestinal zest, increase the drug level of absorption site, improve medicine stability in the gastrointestinal tract, and then improve medicine
Thing bioavailability.
Polymer micelle is the thermodynamic stable system that amphipathic nature polyalcohol spontaneously forms in aqueous.This process
It is to be withdrawn from and be polymerized by hydrophobic patch the free energy causing from aqueous solution to reduce promotion.With low-molecular-weight surfactant phase
Than, the CMC of amphipathic nature polyalcohol is low, and this makes polymer micelle more can resist the dilution of solution to a certain extent, meanwhile, composition
Micelle core hydrophobic patch is tightly combined, it is not easy to dissociate after being diluted by Dali body fluid in physiological environment, stability is more preferable.Glue
Shu Zuowei pharmaceutical carrier has the advantage of uniqueness：Positioned at micelle nuclear location hydrophobic patches as fat-soluble medicine bank,
Can be combined with medicine by chemistry, physics or the effect of electrostatic force, and then play and improve fat-soluble medicine in body
Dissolubility in liquid, avoid its inactivation in biotic environment, change its absorption behavior in vivo.
Amphipathic nature polyalcohol is at least by hydrophilic and lipophilic high molecular polymer dimerous, this kind of polymer at present
Hydrophilic fractions mostly select Polyethylene Glycol (polyethylene glycol, PEG).PEG water solublity is good, has height
Hydration properties, provide enough sterically hindered for micelle.Additionally, its biocompatibility is good, and pass through FDA certification, because
This is widely used as pharmaceutic adjuvant and uses.
Content of the invention
The inventive concept of the present invention：General nanometer is not only had based on the micelle administration system of pegylated phospholipids preparation
The advantage wanting system given by microgranule：Particle diameter is little, substantially between 10nm～1000nm, is a kind of system of dynamic stabilization, a side
Face avoids other particulate delivery systems such as liposome it is easy to assemble pockets of shortcoming；On the other hand medicine can more be improved
Distribution, improves curative effect of medication.Using pegylated phospholipids as carrier material, PEG chain can form parent on the surface of particle
Aqueouss protective layer, can play the advantage of micelle administration system further.At present, the micelle of relevant pegylated phospholipids preparation
As the research of oral delivery system of insulin, all there is not been reported both at home and abroad.On the one hand, prepared by pegylated phospholipids
Micelle can improve the dissolubility of insulin medicament, and on the other hand, the water solublity fragment of micelle can protect a drug from gastric acid
With the destruction of enzyme in digestive tract, and then improve insulin oral administration biaavailability, be a kind of preferable oral administration carrier.
It is an object of the invention to provide a kind of be available for oral insulin micellar preparation.After oral administration, can protect
Insulin quickly passes through intestinal rete malpighii, reduces the degraded of digestive tract proteolytic enzyme, overcomes epithelial barrier, enters blood and follows
Ring, plays hypoglycemic effect.
Therefore, the present invention provide a kind of is available for oral insulin micellar preparation, its contain the insulin of therapeutically effective amount,
Pegylated phospholipids and pharmaceutically acceptable adjuvant, described be available for oral insulin micellar preparation and be preferably enteric
Preparation, more preferably enteric coated capsule preparation.
It is a further object to provide being available for the preparation method of oral insulin micellar preparation.
The invention mainly includes by the use of pegylated phospholipids as major auxiliary burden, using suitable preparation means system
Standby oral insulin micellar preparation.
Pegylated phospholipids in the insulin micellar preparation of the present invention, are conducive to insulin molecule to quickly pass through intestinal
Rete malpighii, reduces insulin molecule contact with proteolytic enzyme in digestive tract, and protection insulin molecule smoothly enters blood and follows
Ring, plays hypoglycemic activity.
Detailed Description Of The Invention
The invention provides a kind of be available for oral insulin micellar preparation, it contains the insulin of therapeutically effective amount, gathers
PEGylation phospholipid and pharmaceutically acceptable adjuvant.
Insulin micelle according to the present invention can be solution form or lyophilized form as needed.
According to the present invention, the mol ratio of described insulin and pegylated phospholipids is 1: 2 to 1: 20, preferably 1: 4 to 1:
10.
The pegylated phospholipids of the present invention pass through the nitrogenous base on covalent bond and phospholipid molecule for peg molecule
It is combined into.
For the pegylated phospholipids of the present invention, the carbon number that in its structure, the fatty acid of phospholipid moiety comprises is 10
～24, preferably 12,14,16,18,20,22,24 carbon atoms, fatty acid chain can be saturation or part
Saturation it is accordingly required in particular to the fatty acid pointed out is lauric acid (12 carbon), myristic acid (14 carbon), Palmic acid (16 carbon), stearic acid
Or Oleic acid or linoleic acid (18 carbon), twenty sour (20 carbon), mountain Yu acid (22 carbon), lignoceric acid (24 carbon).
Pegylated phospholipids, its phospholipid moiety can be phosphatidyl ethanolamine (PE), phosphatidylcholine (PC), phosphatidyl
Inositol (PI), phosphatidyl serine (PS) diphosphatidylglycerol, the sour phospholipid of contracting, lysophosphatidylcholine (LPC), haemolysis ethanolamine phosphorus
Fat (LPE) etc..
Pegylated phospholipids, its molecular weight polyethylene glycol scope is 500～20000 dalton, and preferably Polyethylene Glycol divides
Son amount scope is 1000～10000 dalton, preferred scope 1000～5000 dalton, most preferred peg molecule
Measure as 2000 dalton.
The pegylated phospholipids of the present invention are preferably PEG4000-DSPE
(PEG2000-DSPE).
In the insulin micellar preparation of the present invention, the particle size range of micelle is 5-100nm, preferably 10-50nm, most preferably
10-20nm.
Insulin micellar preparation of the present invention, is as carrier using pegylated phospholipids, by certain system
Agent means, the insulin of therapeutic dose are wrapped in formed micelle, are not added with any absorption enhancers, enzyme level in preparation
Agent etc..
Present invention also offers the preparation method of insulin micellar preparation, it is wrapped in Pegylation phosphorus including by insulin
In the micelle that fat is formed, it is prepared into and is available for oral insulin micellar preparation.
The preparation method of the insulin micellar preparation according to the present invention specifically includes following steps：
(1) insulin is suspended in pure water or dilute hydrochloric acid solution (pH3.0) or dissolves；
(2) pegylated phospholipids are dissolved in pure water；
(3) (1) is mixed with (2), aquation 30-60min at 25-60 DEG C, optimal conditionss complete for 50 DEG C of aquations 30min
Insulin and the dynamical assemble process of micelle.
According to the present invention, the unit dose of insulin is 50-300IU, preferred unit dosage 100-200IU, optimum unit
Dosage is 150IU, and the needs according to each special entity are adjusted by dosage.
In order to be better understood from present disclosure, we are explained as follows to some technical terms.
When " micelle " refers to that amphiphilic concentration in aqueous exceedes critical micelle concentration (CMC), can be spontaneous
Ground polymerization forms micelle.The structure of micelle is different from liposome, does not have the architectural feature of lipid bilayer.In general, micelle
Structure is that hydrophobic part is inside, forms hydrophobic core, hydrophilic segment is outwardly formed water-wetted surface.Micelle particle diameter is little, and mean diameter exists
10～20nm about.Therefore, its not still thermodynamic stable system, and be dynamic stabilization system.In addition, micella particle is not
Easily assemble layering, contain capacity height, can contain higher dose in low concentration.
" phospholipid ", the molecular structure of phospholipid is similar with fat, is except for the difference that only connected with two fatty acids on glycerol molecule,
3rd hydroxyl is combined into fat with phosphoric acid.This structure of phospholipid makes it a kind of amphiphilic, its phosphoric acid or phosphoric acid
Ester one end is polarity, easily inhales with aqueous phase, constitutes the hydrophilic head of phospholipid molecule, and its fatty acid one end is nonpolar
, do not inhale with aqueous phase, constitute the hydrophobic tail of phospholipid molecule.Phospholipid involved in the present invention is mainly polyglycol derivatization
Phospholipid.In the present invention, polyglycol derivatization phospholipid can also be used cooperatively with other phospholipid.
" therapeutically effective amount " refers to that insulin produces the consumption of therapeutic effect.
It is an advantage of the invention that：It is not introduced into any organic solvent during pegylated phospholipids prepare micelle,
Avoid the deactivation of insulin.Lyophilization step no affects on the biological activity of insulin.The mouth of insulin micellar preparation
Take dosage suitably, when normal rat qf oral administration dosage is 50IU/kg, highest blood glucose reduces percentage rate and reaches more than 20%,
There is extensive potential applicability in clinical practice, the serial side effect that the administration of diabeticss long term injections produces can be avoided.And pancreas
The preparation method of island element micelle is simple, instrument and equipment that need not be large-scale, is suitable for commercial production.
Therefore, the insulin micellar preparation of the present invention can be used for oral administration.
In conjunction with embodiment, further detailed description is done to other objects of the present invention and advantage so as to apparent.
Brief description
Fig. 1 is the transmission electron microscope photo of insulin micelle；
Fig. 2 is release figure in the dilute hydrochloric acid solution of pH 2.5 for the insulin micelle；
Fig. 3 is release figure in the phosphate buffer of pH 7.4 for the insulin micelle；
Fig. 4 is insulin molecule form present in micellar preparation；
Fig. 5 is the blood sugar level variation diagram after normal rat duodenal administration.
Specific embodiment
Following examples are mainly used for further illustrating the present invention, rather than limit the scope of the present invention.
The preparation of embodiment 1 INS-PEG2000-DSPE micellar preparation
Preparation prescription is shown in Table 1.
The encapsulation efficiency of table 1 INS-PEG2000-DSPE micelle
| Lipid/medicine (mol/mol) | Medicine (mg/ml) | Envelop rate (%) |
| 2∶1 | 1 | 70.5 |
| 6∶1 | 1 | 99.2 |
| 10∶1 | 1 | 99.3 |
Preparation technology：By the medicine in above-mentioned prescription/fat ratio, weighing insulin (INS) (has purchased from the pharmacy of Xuzhou Wan Bang Golden Bridge
Limit company) it is dissolved in or is suspended in (1mg/ml) in pure water or dilute hydrochloric acid solution, weigh PEG2000-DSPE (purchased from Lipoid) molten
In pure water (20mg/ml), both mixing, stand 60min, then aquation 60min at 37 DEG C, obtains final product and be available for oral islets of langerhans
Plain micellar preparation.Gained sample appearance is in the solution of achromatism and clarity, mean diameter 15nm, particle diameter distribution 10nm-20nm.Above-mentioned
Micellar solution can freeze-dried after lyophilized powder, its Chinese medicine/fat (insulin/phospholipid) mol ratio is the micelle prepared when 1: 6
Transmission electron microscope photo see Fig. 1.
The preparation of embodiment 2 INS-PEG5000-DSPE micellar preparation
Preparation prescription is shown in Table 2.
The encapsulation efficiency of table 2 INS-PEG5000-DSPE micelle
| Lipid/medicine (mol/mol) | Medicine (mg/ml) | Envelop rate (%) |
| 1∶1 | 1 | 65.1 |
| 4∶1 | 1 | 99.4 |
| 8∶1 | 1 | 99.2 |
Preparation technology：By the medicine fat ratio in above-mentioned prescription, weigh INS and be dissolved in or be suspended in pure water or dilute hydrochloric acid solution
(1mg/ml), weigh PEG5000-DSPE (purchased from Lipoid) and be dissolved in pure water (20mg/ml), both mixing, stand 40min,
Then aquation 50min at 45 DEG C, obtains final product and is available for oral insulin micellar preparation.Gained sample appearance is in the molten of achromatism and clarity
Liquid, mean diameter 15nm, particle diameter distribution 10nm-20nm.Above-mentioned micellar solution can freeze-dried after lyophilized powder.
The preparation of embodiment 3INS-PEG10000-DSPE micellar preparation
Preparation prescription is shown in Table 3.
The encapsulation efficiency of table 3INS-PEG10000-DSPE micelle
| Lipid/medicine (mol/mol) | Medicine (mg/ml) | Envelop rate (%) |
| 3∶1 | 1 | 78.1 |
| 8∶1 | 1 | 99.4 |
| 12∶1 | 1 | 99.2 |
Preparation technology：By the medicine fat ratio in above-mentioned prescription, weigh INS and be dissolved in or be suspended in pure water or dilute hydrochloric acid solution
(1mg/ml), weigh PEG10000-DSPE (purchased from Lipoid) and be dissolved in pure water (20mg/ml), both mixing, stand 40min,
Then aquation 30min at 55 DEG C, obtains final product and is available for oral insulin micellar preparation.Gained sample appearance is in the molten of achromatism and clarity
Liquid, mean diameter 15nm, particle diameter distribution 10nm-20nm.Above-mentioned micellar solution can freeze-dried after lyophilized powder.
The extracorporeal releasing test of embodiment 4INS-PEG2000-DSPE micelle
PEG2000-DSPE micelle (the medicine/fat ratio prepared from the method according to above example using Determination by Stripping INS
1: 4) speed of release in, HPLC detects.The INS-PEG2000-DSPE preparing micelle 1ml (1mg/ml) is placed in bag filter
In (Beijing is through Bioisystech Co., Ltd of HTC of section, molecular cut off 14,000), the bag filter fastened is placed in drug-eluting
Instrument (model ZRS-8G, Radio Factory of Tianjin Univ.) turn in basket, dissolution medium be respectively 150ml dilute hydrochloric acid solution (pH
2.5) with PBS (pH 7.6), each sample is parallel to do three, in 37 DEG C, 50rpm, respectively at 1,2,3,4h sampling, often
The secondary dissolution medium 0.2ml taking 0.2ml dissolution medium, mending fresh 37 DEG C.Reference standard curve, tries to achieve release percentage rate.Islets of langerhans
Stripping curve from micelle for the element is shown in Fig. 2 and Fig. 3 respectively.
The existence form of embodiment 5 insulin molecule
Will be molten with the PBS of insulin for the INS-PEG5000-DSPE micellar solution being prepared according to the method for above example
The each 1ml of liquid (1mg/ml) is put in the high scheming of analytical type high speed respectively, rotating speed 60000rpm, is centrifuged 6h altogether, and analysis result shows (figure
4)：In insulin solutions, insulin molecule is mainly existed with dimer and six dimer form, and in insulin micellar solution
Middle insulin molecule is mainly existed with single dimer form.
The pharmacological experiment of embodiment 6 insulin micellar preparation
Take healthy male SD rat (purchased from Beijing Vital River Experimental Animals Technology Co., Ltd.) 15, body weight 180-
200g, is randomly divided into 3 groups, and first group gives insulin PBS solution (200IU kg-1), and second and third group gives INS- respectively
PEG2000-DSPE micelle, dosage is respectively 50IU kg-1With 200IU kg-1.Fasting 16h before experiment, can free water.Abdomen
Pentobarbital sodium anesthetized rat is injected in chamber, subsequently rat abdomen is fixed on flat board upward, opens abdominal cavity along rat ventrimeson,
Duodenal administration, concrete operations are as follows：In drug administration by injection at pylorus about 5cm.In order to avoid solution is excessive, should adopt as far as possible
Small gauge needles, and along the downward drug administration by injection in intestinal direction.Subsequently rat abdomen is carried out operation stitching, respectively at 0,1,2,3,
4th, 5,6,7,8, take blood in rat tail vein after 10h, measure blood glucose value (Fig. 5) with blood glucose meter (three promises are stable).As seen from the figure,
The change of blood sugar of insulin solutions group with administration before basically identical, the blood sugar level of the insulin micellar preparation group of high and low dose
Significantly lower than insulin solutions group, and blood sugar level maintains downward trend in 3-8h, and floor level drops in high and low dose group blood glucose
Respectively may be about the 35% and 23% about of initial value, subsequent blood glucose begins to ramp up.Result shows, normal rat duodenum gives
After insulin micellar preparation, there is obvious hypoglycemic activity.
Claims (7)
1. a kind of be available for oral insulin micellar preparation, comprise insulin, pegylated phospholipids, and pharmaceutically acceptable
Adjuvant, wherein, the mol ratio of described insulin and pegylated phospholipids is 1: 2 to 1: 20, described Pegylation phosphorus
Fat is PEG4000-DSPE；
The preparation method of described insulin micellar preparation is：
(1) insulin is suspended in the diluted hydrochloric acid aqueous solution of water or pH 3.0 or dissolves；
(2) pegylated phospholipids are dissolved in water；
(3) (1) is mixed with (2), aquation 30-60min at 25 DEG C -60 DEG C, obtain insulin micelle.
2. micellar preparation according to claim 1, the mol ratio of wherein said insulin and pegylated phospholipids is 1: 4
To 1: 10.
3. micellar preparation according to claim 1 and 2, described micellar preparation is solution form or lyophilized form.
4. micellar preparation according to claim 1 and 2, wherein said micellar preparation is enteric coated preparation.
5. micellar preparation according to claim 4, wherein said enteric coated preparation is enteric coated capsule preparation.
6. application in preparing oral hypoglycaemic medicine for the micellar preparation according to any one of claim 1-5.
7. a kind of method preparing micellar preparation described in any one of claim 1-5, comprises the following steps：
(1) insulin is suspended in the diluted hydrochloric acid aqueous solution of water or pH 3.0 or dissolves；
(2) pegylated phospholipids are dissolved in water；
(3) (1) is mixed with (2), aquation 30-60min at 25 DEG C -60 DEG C, obtain insulin micelle.
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