CN106138011B - Calcium carbonate/hyaluronic acid combination drug carrier and preparation method thereof - Google Patents
Calcium carbonate/hyaluronic acid combination drug carrier and preparation method thereof Download PDFInfo
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- CN106138011B CN106138011B CN201610635085.XA CN201610635085A CN106138011B CN 106138011 B CN106138011 B CN 106138011B CN 201610635085 A CN201610635085 A CN 201610635085A CN 106138011 B CN106138011 B CN 106138011B
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- hyaluronic acid
- calcium
- calcium carbonate
- drug carrier
- combination drug
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- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 title claims abstract description 133
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 88
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 87
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 87
- 229910000019 calcium carbonate Inorganic materials 0.000 title claims abstract description 66
- 239000003937 drug carrier Substances 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- 229940000425 combination drug Drugs 0.000 title claims abstract description 24
- 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 abstract description 184
- 102000004877 Insulin Human genes 0.000 claims abstract description 92
- 108090001061 Insulin Proteins 0.000 claims abstract description 92
- 229940125396 insulin Drugs 0.000 claims abstract description 92
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 41
- OVBPIULPVIDEAO-LBPRGKRZSA-N Folic acid Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims abstract description 38
- 239000004094 surface-active agent Substances 0.000 claims abstract description 31
- 239000006210 lotion Substances 0.000 claims abstract description 28
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000003814 drug Substances 0.000 claims abstract description 27
- 229960000304 folic acid Drugs 0.000 claims abstract description 27
- 235000019152 folic acid Nutrition 0.000 claims abstract description 27
- 239000011724 folic acid Substances 0.000 claims abstract description 27
- 238000003756 stirring Methods 0.000 claims abstract description 21
- 239000002245 particle Substances 0.000 claims abstract description 18
- 239000007864 aqueous solution Substances 0.000 claims abstract description 17
- 125000003929 folic acid group Chemical group 0.000 claims abstract description 16
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910001424 calcium ion Inorganic materials 0.000 claims abstract description 14
- 239000011575 calcium Substances 0.000 claims abstract description 7
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims abstract description 5
- 239000006185 dispersion Substances 0.000 claims abstract 2
- 239000008367 deionised water Substances 0.000 claims description 29
- 229910021641 deionized water Inorganic materials 0.000 claims description 29
- 239000002253 acid Substances 0.000 claims description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Natural products OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 14
- 239000002105 nanoparticle Substances 0.000 claims description 12
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 11
- 239000004227 calcium gluconate Substances 0.000 claims description 11
- 229960004494 calcium gluconate Drugs 0.000 claims description 11
- 235000013927 calcium gluconate Nutrition 0.000 claims description 11
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 9
- 150000002500 ions Chemical class 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 9
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 8
- -1 Sorbitan fatty ester Chemical class 0.000 claims description 8
- 239000001099 ammonium carbonate Substances 0.000 claims description 8
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 claims description 8
- 239000001527 calcium lactate Substances 0.000 claims description 8
- 229960002401 calcium lactate Drugs 0.000 claims description 8
- 235000011086 calcium lactate Nutrition 0.000 claims description 8
- 125000005456 glyceride group Chemical group 0.000 claims description 8
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims description 7
- 239000001639 calcium acetate Substances 0.000 claims description 7
- 235000011092 calcium acetate Nutrition 0.000 claims description 7
- 229960005147 calcium acetate Drugs 0.000 claims description 7
- 239000001110 calcium chloride Substances 0.000 claims description 7
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 7
- 229960002713 calcium chloride Drugs 0.000 claims description 7
- 235000011148 calcium chloride Nutrition 0.000 claims description 7
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 3
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 claims description 2
- 239000001587 sorbitan monostearate Substances 0.000 claims description 2
- 235000011076 sorbitan monostearate Nutrition 0.000 claims description 2
- 229940035048 sorbitan monostearate Drugs 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000005034 decoration Methods 0.000 claims 1
- 235000014113 dietary fatty acids Nutrition 0.000 claims 1
- 239000000194 fatty acid Substances 0.000 claims 1
- 229930195729 fatty acid Natural products 0.000 claims 1
- 239000007788 liquid Substances 0.000 abstract description 11
- 239000000463 material Substances 0.000 abstract description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052791 calcium Inorganic materials 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 238000009938 salting Methods 0.000 abstract 2
- 239000000243 solution Substances 0.000 description 42
- 239000002539 nanocarrier Substances 0.000 description 11
- 238000009826 distribution Methods 0.000 description 9
- 239000011259 mixed solution Substances 0.000 description 8
- 206010012601 diabetes mellitus Diseases 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 159000000007 calcium salts Chemical class 0.000 description 5
- 238000005253 cladding Methods 0.000 description 5
- 230000002218 hypoglycaemic effect Effects 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 102000057297 Pepsin A Human genes 0.000 description 4
- 108090000284 Pepsin A Proteins 0.000 description 4
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 4
- 230000002467 anti-pepsin effect Effects 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 4
- 210000000496 pancreas Anatomy 0.000 description 4
- 229940111202 pepsin Drugs 0.000 description 4
- 239000012266 salt solution Substances 0.000 description 4
- 230000032258 transport Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 229960005069 calcium Drugs 0.000 description 3
- 210000001842 enterocyte Anatomy 0.000 description 3
- 210000000981 epithelium Anatomy 0.000 description 3
- 210000004211 gastric acid Anatomy 0.000 description 3
- 229940125395 oral insulin Drugs 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000009738 saturating Methods 0.000 description 3
- 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 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- HVUMOYIDDBPOLL-XGKPLOKHSA-N [2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XGKPLOKHSA-N 0.000 description 2
- 238000005576 amination reaction Methods 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 239000002285 corn oil Substances 0.000 description 2
- 235000005687 corn oil Nutrition 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000004519 grease Substances 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 229920000867 polyelectrolyte Polymers 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000004088 simulation Methods 0.000 description 2
- 239000003549 soybean oil Substances 0.000 description 2
- 235000012424 soybean oil Nutrition 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 208000017667 Chronic Disease Diseases 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 206010018473 Glycosuria Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 235000019774 Rice Bran oil Nutrition 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- FYHXNYLLNIKZMR-UHFFFAOYSA-N calcium;carbonic acid Chemical compound [Ca].OC(O)=O FYHXNYLLNIKZMR-UHFFFAOYSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 229910052806 inorganic carbonate Inorganic materials 0.000 description 1
- 239000010977 jade Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000003232 mucoadhesive effect Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000011241 protective layer Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 239000008165 rice bran oil Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to drug carrier material technical fields, and in particular to calcium carbonate/hyaluronic acid combination drug carrier is made of kernel and clad, and kernel is the porous nano calcium carbonate particle for loading insulin medicament, and clad is the hyaluronic acid of modified with folic acid.The invention also discloses calcium carbonate/hyaluronic acid combination drug carrier preparation methods, the following steps are included: 1) at room temperature, insulin medicament is dissolved in water, then insulin medicament aqueous dispersion is made to w/o type lotion in the oily phase containing surfactant；2) water-soluble calcium salting liquid and water soluble carbonate salting liquid are prepared；3) aqueous solution of calcium ion and carbanion is slowly instilled to the w/o type lotion respectively, controls the micro excess of calcium ion；4) hyaluronic acid aqueous solution is prepared, hyaluronic acid aqueous solution is slowly instilled to lotion made from step 3), stirs and is centrifugally separating to obtain combination drug carrier；Preparation method is simple, is able to achieve large-scale production.
Description
Technical field
The invention belongs to drug carrier material technical fields, and in particular to calcium carbonate/hyaluronic acid combination drug carrier and
Preparation method.
Background technique
Diabetes (Diabetes) are a worldwide public health problems, seriously threaten the mankind health with
Life, there are about 4.15 hundred million adults to suffer from different degrees of diabetes for the whole world in 2015, and also maintains rapid growth
Trend, and Chinese Adult diabetic's quantity has reached 1.09 hundred million people, accounts for about the 26.3% of global diabetic.Glycosuria
Disease is easy the excessive chronic disease of accumulation, clinically with " hyperglycemia " for main feature, blood glucose as a kind of glucose in blood
Control it is lifelong with diabetic, due to hypoinsulinism in blood or there are insulin antibodies, lead to pancreas islet
Element is opposite or absolutely lacks, and the control for blood sugar in diabetic patients level, most directly, effectively administration mode is subcutaneous or quiet
Arteries and veins insulin injection.But there are many deficiencies for this administration mode, such as: due to the half-life short (3~5 of insulin in blood
Minute), only have small part insulin to can enter liver after blood circulation of human body and plays hypoglycemic effect.In order to ensure hypoglycemic
Effect, long-term, frequent insulin injection is needed, to cause body, spirit and multiple pressure economically to patient.
Oral insulin can avoid pain caused by injection of insulin well, and drug oral delivering need to be transported through gastrointestinal tract
Defeated, mucoadhesive and enterocyte transport three processes, and the oral delivery of insulin must overcome the extreme pH of gastric acid, digestion simultaneously
The multiple carrying barriers such as enzyme degradation, enterocinesia removing and enteric epithelium absorption.Insulin is a kind of protein, it is easy to by stomach
Protease dissolution, therefore, the task of top priority needs to develop a kind of insulin load that pharmaceutical carrier is used for, it is helped to overcome these loads
Fortune barrier achievees the purpose that carrying delivering is the key that realize oral insulin.
Application No. is 201210460333.3 Chinese invention patent, the invention discloses one kind to have synergistic antitumor effect
The bio-compatible Nano medication complex carrier answered, drug and preparation method thereof.It is provided by the present invention by core, the cladding core
The articulamentum of core and the shell composition of the cladding articulamentum；The core is to have adsorbed the degradable multiporous nothing of anticancer drug
Machine nanoparticle, the articulamentum are made of polyelectrolyte, and by protein and polyelectrolyte, alternate group fills structure to the shell layer by layer
At the protein is selected from one of tumor necrosis factor superfamily member.The pharmaceutical carrier is in the presence of structure is complicated, insulin load
The deficiencies of not firm.
Summary of the invention
The purpose of the present invention is to solve the above problem, provide a kind of calcium carbonate/hyaluronic acid combination drug carrier and
Preparation method.
In order to achieve the above object of the invention, the invention adopts the following technical scheme:
A kind of calcium carbonate/hyaluronic acid combination drug carrier, the pharmaceutical carrier are made of kernel and clad, described interior
Core is the porous nano calcium carbonate particle for loading insulin medicament, and the clad is the hyaluronic acid of modified with folic acid.
Preferably, the partial size of the Nano particles of calcium carbonate is 80~180nm, and it is glutinous in enteric epithelium to be conducive to combination drug carrier
Absorption, infiltration in film and the transhipment in enterocyte.
Preferably, the clad with a thickness of 15~35nm.
A kind of preparation method of calcium carbonate/hyaluronic acid combination drug carrier, comprising the following steps: 1) at room temperature, by pancreas
Island element drug is dissolved in water, and compound concentration is the insulin medicament aqueous solution of 0.01~0.1mol/L, then by insulin medicament water
Solution is scattered in the oily phase containing surfactant, and after stirring 30min, w/o type lotion is made；It 2) at room temperature, will be water-soluble
Calcium salt is dissolved in deionized water, prepares the aqueous solution that calcium ion concentration is 0.01~0.5mol/L；Water soluble carbonate is dissolved in
Ionized water prepares the aqueous solution that carbon acid ion concentration is 0.01~0.5mol/L；3) by the water of calcium ion and carbanion
Solution slowly instills the w/o type lotion respectively, controls the micro excess of calcium ion, stirs 30min；4) hyalomitome sour water is prepared
Hyaluronic acid aqueous solution is slowly instilled lotion made from step 3) by solution, after stirring 30min, is centrifugated to get carbon is arrived
Sour calcium/hyaluronic acid combination drug carrier.
Preferably, the surfactant is w/o type, concentration of the surfactant in oily phase be 0.05~
2.0wt%, the surfactant select sorbitan fatty ester, sorbitan monostearate, monostearate
One of glyceride or citric acid fatty glyceride are a variety of.
Preferably, the water-soluble Ca salt selects one of calcium gluconate, calcium lactate, calcium chloride or calcium acetate or more
Kind.
Preferably, the water soluble carbonate selects the one or more of sodium carbonate, potassium carbonate or ammonium carbonate.
Preferably, the concentration of the hyaluronic acid aqueous solution is 0.05~2.0wt%.
Preferably, the hyaluronic acid is the hyaluronic acid of modified with folic acid.
Compared with prior art, the present invention beneficial effect is: calcium carbonate of the invention/hyaluronic acid combination drug carrier, with
Material based on porous, inorganic nanometer calcium carbonate, the load for insulin medicament；Then make under calcium ion effect with leaf
The hyaluronic acid of the induced transports function base such as acid modification is surface-crosslinked in calcium base nano-carrier, forms protective layer, delays oral
Gastric acid, pepsin enter carrier and destroy the bioactivity of drug in the process；Make in the stimulation of folic acid induced transport function base
Under, transmission mechanism can be excited, promote absorption of the combination drug carrier in enteric epithelium mucous membrane, infiltration and in enterocyte
Transhipment.Relative insulin drug administration by injection has and the side such as reduces wound, promote drug effect, simplify treatment process, mitigate patient suffering
The advantage in face.Calcium carbonate of the invention/hyaluronic acid combination drug carrier preparation method is simple, large-scale production easy to accomplish.
Detailed description of the invention
Fig. 1 is the synthesis schematic diagram of modified with folic acid hyaluronic acid of the present invention.
Fig. 2 is the scanning electron microscope (SEM) photograph of 1 calcium carbonate nano particle of the embodiment of the present invention.
Fig. 3 is the projection electron microscope of 1 calcium carbonate nano particle of the embodiment of the present invention.
Fig. 4 is the projection electron microscope of 1 folic acid modification hyaluronic acid coated caco3 nanoparticle of the embodiment of the present invention.
Fig. 5 is 1 calcium carbonate nano particle of the embodiment of the present invention, calcium carbonate/hyaluronic acid combination drug carrier laser particle size
Distribution map.
Fig. 6 is 1 calcium carbonate of the embodiment of the present invention/hyaluronic acid complex insulin pharmaceutical carrier hypoglycemic work in Mice Body
Use effect picture.
Fig. 7 is 3 insulin load of embodiment of the present invention antipepsin effect picture in different pharmaceutical carrier.
Specific embodiment
Below by specific embodiment the technical scheme of the present invention will be further described explanation.
Fig. 1 is the synthesis schematic diagram of modified with folic acid hyaluronic acid: firstly, with dimethyl sulfoxide (DMSO) for solvent,
1.0mmol folic acid (FA) is living under the action of catalyst dicyclohexylcarbodiimide (DCC) and N- hydroxysuccinimide (NHS)
Change, generates amination folic acid (FA-NH with 10.0mmol ethylenediamine2)；Then, the hyaluronic acid (HA) of 1.0mmol with
0.30mmol amination folic acid (FA-NH2) amidation is carried out under DCC/NHS catalytic action, modified with folic acid is prepared
Hyaluronic acid (FA-HA), modified hyaluronic acid has the function of induced transport.
Embodiment 1:
The calcium carbonate of the present embodiment/hyaluronic acid complex insulin pharmaceutical carrier preparation method, includes the following steps:
(1) sodium carbonate is dissolved in deionized water, it is molten that preparation obtains the sodium carbonate that carbon acid ion concentration is 0.1mol/L
Liquid；Calcium chloride is dissolved in deionized water, prepares and obtains the calcium chloride solution that calcium ion concentration is 0.12mol/L, prepare and complete
It is spare afterwards；
(2) hyaluronic acid of modified with folic acid is dissolved in deionized water, prepares and obtains the hyalomitome that mass percent is 1%
Acid solution, it is spare after the completion of preparation；
(3) insulin is dissolved in the buffered aqueous solution of pH=2.0, compound concentration is that the insulin of 0.01mol/L is molten
Liquid then adjusts the pH to 8.0 of insulin solutions by buffer；
(4) the oily phase containing surfactant is prepared, by surfactant sorbitan fatty ester (Span-80) point
It dissipates in edible peanut oil, obtains the oily phase for the sorbitan fatty ester (Span-80) that mass percent is 1%；Room
Under temperature, the insulin solutions that 1mL step (3) obtains are added in oily phase of the 20mL containing surfactant, and stirring forms w/o type cream
Liquid；
(5) at room temperature, 0.50mL sodium carbonate liquor and 0.50mL calcium chloride solution are slowly dropped into the W/ of above-mentioned (4) simultaneously
In O-shaped lotion, it is stirred continuously during dropwise addition；
(6) at room temperature, the hyaluronic acid solution of 1mL step (2) modified with folic acid is slowly dropped into the lotion of step (5),
It is stirred continuously during dropwise addition, continues to stir 30min after being added dropwise to complete, be then centrifuged for separating multiple up to calcium carbonate/hyaluronic acid
Close insulin medicament nano-carrier.
As shown in Figure 2-5, the calcium carbonate of the present embodiment/hyaluronic acid complex insulin pharmaceutical carrier is by kernel and clad
Composition, kernel are the porous nano calcium carbonate particle of load insulin, and clad is hyaluronic acid.Fig. 2 and Fig. 3 is load respectively
The scanning electron microscope (SEM) photograph and transmission electron microscope picture of the calcium carbonate nano particle of insulin, it can be seen that the size of calcium carbonate nano particle point
Cloth is uniform, and particle diameter distribution is between 80~180nm；Fig. 4 and Fig. 5 is respectively that calcium carbonate/hyaluronic acid complex insulin drug carries
The transmission electron microscope picture and Laser particle-size distribution figure of body, it is known that coat one layer of organic layer, organic layer in inorganic carbonate calcium nanoparticle
With a thickness of 15~35nm, diameter of carrier further increases.
Fig. 6 is for calcium carbonate/hyaluronic acid complex insulin medicament nano carrier small by way of oral or injection
The effect of hypoglycemic effect compares figure in mouse body, it is known that relative to direct oral insulin and subcutaneous insulin injections, calcium carbonate/
Hyaluronic acid complex insulin medicament nano carrier can effectively improve the hypoglycemic effect effect of insulin, can reach and subcutaneously infuse
Penetrate the comparable blood sugar decreasing effect of mode.
Embodiment 2:
The calcium carbonate of the present embodiment/hyaluronic acid complex insulin pharmaceutical carrier preparation method, includes the following steps:
(1) sodium carbonate is dissolved in deionized water, it is molten that preparation obtains the sodium carbonate that carbon acid ion concentration is 0.1mol/L
Liquid；Calcium chloride is dissolved in deionized water, prepares and obtains the calcium chloride solution that calcium ion concentration is 0.12mol/L, prepare and complete
It is spare afterwards；
(2) hyaluronic acid of modified with folic acid is dissolved in deionized water, prepares and obtains the hyalomitome that mass percent is 2%
Acid solution, it is spare after the completion of preparation；
(3) insulin is dissolved in the buffered aqueous solution of pH=2.0, compound concentration is that the insulin of 0.01mol/L is molten
Liquid then adjusts the pH to 8.0 of insulin solutions by buffer；
(4) the oily phase containing surfactant is prepared, by surfactant sorbitan fatty ester (Span-80) point
It dissipates in edible peanut oil, obtains the oily phase for the sorbitan fatty ester (Span-80) that mass percent is 1%；Room
Under temperature, the insulin solutions that 1mL step (3) obtains are added in oily phase of the 20mL containing surfactant, and stirring forms w/o type cream
Liquid；
(5) at room temperature, 0.50mL sodium carbonate liquor and 0.50mL calcium chloride solution are slowly dropped into the W/ of above-mentioned (4) simultaneously
In O-shaped lotion, it is stirred continuously during dropwise addition；
(6) at room temperature, the hyaluronic acid solution of 1mL step (2) modified with folic acid is slowly dropped into the lotion of step (5),
It is stirred continuously during dropwise addition, continues to stir 30min after being added dropwise to complete, be then centrifuged for separating multiple up to calcium carbonate/hyaluronic acid
Close insulin medicament nano-carrier.
The calcium carbonate of the present embodiment/hyaluronic acid complex insulin pharmaceutical carrier is made of kernel and clad, and kernel is
The porous nano calcium carbonate particle of load insulin, for particle diameter distribution between 80~180nm, clad is hyaluronic acid, cladding
Layer with a thickness of 20~35nm.
Embodiment 3:
To calcium carbonate made from embodiment 1, embodiment 2/hyaluronic acid complex insulin pharmaceutical carrier, simple pancreas islet
Element, insulin load carry out the simulated experiment in gastric juice, the insulin etc. in above four kinds of materials on calcium carbonate nano particle
The load capacity of amount, insulin is 0.3 μ g, four kinds of materials is mixed with the simulation hydrochloric acid solution of 3mL pH=1.2, simulation hydrochloric acid is molten
The pepsin for being 3g/L containing mass concentration in liquid, after 37 DEG C of culture 30min, the 0.1mol/L NaOH that 0.2mL is added is terminated
The activity of pepsin.Fig. 7 is that antipepsin acts on retention figure to insulin in varied situations, and simple insulin is complete
It is dissolved entirely by pepsin, insulin load can improve the function and effect of antipepsin in calcium carbonate nano particle；In carbonic acid
Calcium nano-carrier outer cladding hyaluronic acid can delay the destruction to carrier and drug molecule such as digestive ferment, gastric acid, and hyaluronic acid
Concentration it is higher, clad is thicker, and the antipepsin effect of pharmaceutical carrier is better.
Embodiment 4:
The calcium carbonate of the present embodiment/hyaluronic acid complex insulin pharmaceutical carrier preparation method, includes the following steps:
(1) sodium carbonate, potassium carbonate and ammonium carbonate are dissolved in deionized water, preparation obtains carbon acid ion concentration and is
The carbonic acid mixed salt solution of 0.5mol/L；Calcium gluconate, calcium lactate, calcium chloride and calcium acetate are dissolved in deionized water, matched
The calcium salt mixed solution that calcium ion concentration is 0.5mol/L is made, it is spare after the completion of preparation；
(2) hyaluronic acid of modified with folic acid is dissolved in deionized water, prepare obtain mass percent be 0.05% it is saturating
Bright matter acid solution, it is spare after the completion of preparation；
(3) insulin being dissolved in the deionized water that pH is 2.0, compound concentration is the insulin solutions of 0.1mol/L,
The pH to 8.0 of insulin solutions is then adjusted by buffer；
(4) the oily phase containing surfactant is prepared, disperses edible soybean oil for surfactant glycerin monostearate
In, obtain the oily phase for the glycerin monostearate that mass percent is 0.5%；At room temperature, the pH that 1mL step (3) obtains is 8.0
Insulin solutions be added oily phase of the 20mL containing surfactant in, stirring form w/o type lotion；
(5) at room temperature, 0.25mL carbonic acid mixed salt solution and 0.3mL calcium salt mixed solution are slowly dropped into simultaneously above-mentioned
(4) it in w/o type lotion, is stirred continuously during dropwise addition；
(6) at room temperature, the hyaluronic acid solution that 1mL step (2) obtains is slowly dropped into the lotion of step (5), is being dripped
It is stirred continuously during adding, continues to stir 30min after being added dropwise to complete, be then centrifuged for separating up to the compound pancreas of calcium carbonate/hyaluronic acid
Island element medicament nano carrier.
The calcium carbonate of the present embodiment/hyaluronic acid complex insulin pharmaceutical carrier is made of kernel and clad, and kernel is
The porous nano calcium carbonate particle of load insulin, for particle diameter distribution between 100~160nm, clad is hyaluronic acid, cladding
Layer with a thickness of 15~20nm.
Embodiment 5:
The calcium carbonate of the present embodiment/hyaluronic acid complex insulin pharmaceutical carrier preparation method, includes the following steps:
(1) ammonium carbonate is dissolved in deionized water, it is molten that preparation obtains the ammonium carbonate that carbon acid ion concentration is 0.2mol/L
Liquid；Calcium gluconate is dissolved in deionized water, prepares and obtains the calcium gluconate solution that calcium ion concentration is 0.2mol/L, match
It is spare after the completion of system；
(2) hyaluronic acid of modified with folic acid is dissolved in deionized water, prepare obtain mass percent be 1.5% it is transparent
Matter acid solution, it is spare after the completion of preparation；
(3) insulin being dissolved in the deionized water that pH is 2.0, compound concentration is the insulin solutions of 0.1mol/L,
The pH to 8.0 of insulin solutions is then adjusted by buffer；
(4) the oily phase containing surfactant is prepared, by surfactant sorbitan monostearate (Span-60) point
It dissipates in edible corn oil, obtains the oily phase for the sorbitan monostearate (Span-60) that mass percent is 1.5%；
At room temperature, the insulin solutions that the pH that 1mL step (3) obtains is 8.0 are added in oily phase of the 25mL containing surfactant, stir shape
At w/o type lotion；
(5) at room temperature, 0.5mL sal volatile and 0.7mL calcium gluconate solution are slowly dropped into above-mentioned (4) simultaneously
In w/o type lotion, it is stirred continuously during dropwise addition；
(6) at room temperature, the hyaluronic acid solution that 0.8mL step (2) obtains is slowly dropped into the lotion of step (5),
It is stirred continuously during being added dropwise, continues to stir 30min after being added dropwise to complete, be then centrifuged for separating compound up to calcium carbonate/hyaluronic acid
Insulin medicament nano-carrier.
The calcium carbonate of the present embodiment/hyaluronic acid complex insulin pharmaceutical carrier is made of kernel and clad, and kernel is
The porous nano calcium carbonate particle of load insulin, for particle diameter distribution between 80~160nm, clad is the transparent of folic acid modification
Matter acid, clad with a thickness of 15~30nm.
Embodiment 6:
The calcium carbonate of the present embodiment/hyaluronic acid complex insulin pharmaceutical carrier preparation method, includes the following steps:
(1) ammonium carbonate, potassium carbonate are dissolved in deionized water, preparing and obtaining carbon acid ion concentration is 0.01mol/L's
Ammonium carbonate and potassium carbonate mixed solution；Calcium gluconate and calcium lactate are dissolved in deionized water, preparation obtains concentration and is
The calcium gluconate and calcium lactate mixed solution of 0.01mol/L, it is spare after the completion of preparation；
(2) hyaluronic acid of modified with folic acid is dissolved in deionized water, prepare obtain mass percent be 0.05% it is saturating
Bright matter acid solution, it is spare after the completion of preparation；
(3) insulin being dissolved in the deionized water that pH is 2.0, compound concentration is the insulin solutions of 0.05mol/L,
The pH to 8.0 of insulin solutions is then adjusted by buffer；
(4) the oily phase containing surfactant is prepared, surfactant citric acid fatty glyceride and monostearate is sweet
Grease is scattered in edible corn oil, and it is sweet for 0.05% citric acid fatty glyceride and monostearate to obtain mass percent
The oily phase of grease；At room temperature, 25mL is added containing surfactant in the insulin solutions that the pH that 1.2mL step (3) obtains is 8.0
In oily phase, stirring forms w/o type lotion；
(5) at room temperature, 0.7mL ammonium carbonate and potassium carbonate mixed solution and 0.9mL calcium gluconate and calcium lactate are mixed
Solution is slowly dropped into the w/o type lotion of above-mentioned (4) simultaneously, is stirred continuously during dropwise addition；
(6) at room temperature, the hyaluronic acid solution that 1.2mL step (2) obtains is slowly dropped into the lotion of step (5),
It is stirred continuously during being added dropwise, continues to stir 30min after being added dropwise to complete, be then centrifuged for separating compound up to calcium carbonate/hyaluronic acid
Insulin medicament nano-carrier.
The calcium carbonate of the present embodiment/hyaluronic acid complex insulin pharmaceutical carrier is made of kernel and clad, and kernel is
The porous nano calcium carbonate particle of load insulin, for particle diameter distribution between 100~180nm, clad is the saturating of folic acid modification
Bright matter acid, clad with a thickness of 15~25nm.
Embodiment 7:
The calcium carbonate of the present embodiment/hyaluronic acid complex insulin pharmaceutical carrier preparation method, includes the following steps:
(1) potassium carbonate is dissolved in deionized water, it is molten that preparation obtains the potassium carbonate that carbon acid ion concentration is 0.01mol/L
Liquid；Calcium acetate is dissolved in deionized water, prepares and obtains the calcium acetate solution that concentration is 0.02mol/L, it is spare after the completion of preparation；
(2) hyaluronic acid of modified with folic acid is dissolved in deionized water, prepare obtain mass percent be 1.3% it is transparent
Matter acid solution, it is spare after the completion of preparation；
(3) insulin being dissolved in the deionized water that pH is 2.0, compound concentration is the insulin solutions of 0.1mol/L,
The pH to 8.0 of insulin solutions is then adjusted by buffer；
(4) the oily phase containing surfactant is prepared, disperses edible jade for surfactant citric acid fatty glyceride
In rice bran oil, the oily phase for the citric acid fatty glyceride that mass percent is 2% is obtained；At room temperature, 1.5mL step (3) obtains
PH be 8.0 insulin solutions be added oily phase of the 35mL containing surfactant in, stirring form w/o type lotion；
(5) at room temperature, 0.6mL solution of potassium carbonate and 0.5mL calcium acetate solution are slowly dropped into the W/O of above-mentioned (4) simultaneously
In type lotion, it is stirred continuously during dropwise addition；
(6) at room temperature, the hyaluronic acid solution that 1.0mL step (2) obtains is slowly dropped into the lotion of step (5),
It is stirred continuously during being added dropwise, continues to stir 30min after being added dropwise to complete, be then centrifuged for separating compound up to calcium carbonate/hyaluronic acid
Insulin medicament nano-carrier.
The calcium carbonate of the present embodiment/hyaluronic acid complex insulin pharmaceutical carrier is made of kernel and clad, and kernel is
The porous nano calcium carbonate particle of load insulin, for particle diameter distribution between 90~180nm, clad is the transparent of folic acid modification
Matter acid, clad with a thickness of 20~30nm.
Embodiment 8:
The calcium carbonate of the present embodiment/hyaluronic acid complex insulin pharmaceutical carrier preparation method, includes the following steps:
(1) select calcium gluconate, calcium lactate, calcium chloride, one of calcium acetate or it is a variety of be dissolved in deionized water, prepare
Carbon acid ion concentration is the carbonic acid mixed salt solution of 0.01mol/L；Select calcium gluconate, calcium lactate, calcium chloride or acetic acid
One of calcium or a variety of calcium salt mixed solutions for being dissolved in deionized water, preparing that calcium ion concentration is 0.02mol/L, prepare and complete
It is spare afterwards；
(2) hyaluronic acid of modified with folic acid is dissolved in deionized water, prepare obtain mass percent be 1.8% it is transparent
Matter acid solution, it is spare after the completion of preparation；
(3) insulin being dissolved in the deionized water that pH is 2.0, compound concentration is the insulin solutions of 0.08mol/L,
The pH to 8.0 of insulin solutions is then adjusted by buffer；
(4) the oily phase containing surfactant is prepared, surfactant selects sorbitan fatty ester, D-sorbite
One of acid anhydride monostearate, glycerin monostearate or citric acid fatty glyceride are a variety of, by surfactant point
It dissipates in edible soybean oil, obtains the oily phase for the surfactant for being 0.8% containing mass percent；At room temperature, 1.0mL step
(3) insulin solutions that the pH obtained is 8.0 are added in oily phase of the 30mL containing surfactant, and stirring forms w/o type lotion；
(5) at room temperature, 0.6mL carbonic acid mixed salt solution and 0.5mL calcium salt mixed solution are slowly dropped into above-mentioned (4) simultaneously
W/o type lotion in, be stirred continuously during dropwise addition；
(6) at room temperature, the hyaluronic acid solution that 1.0mL step (2) obtains is slowly dropped into the lotion of step (5),
It is stirred continuously during being added dropwise, continues to stir 30min after being added dropwise to complete, be then centrifuged for separating compound up to calcium carbonate/hyaluronic acid
Insulin medicament nano-carrier.
The calcium carbonate of the present embodiment/hyaluronic acid complex insulin pharmaceutical carrier is made of kernel and clad, and kernel is
The porous nano calcium carbonate particle of load insulin, for particle diameter distribution between 80~140nm, clad is the transparent of folic acid modification
Matter acid, clad with a thickness of 20~35nm.
If raw material employed in the embodiment of the present invention is raw material commonly used in the art without specified otherwise, implement
Method employed in example, is the conventional method of this field.
The preferred embodiment of the present invention and principle are described in detail above, to those skilled in the art
Speech, the thought provided according to the present invention will change in specific embodiment, and these changes also should be regarded as the present invention
Protection scope.
Claims (8)
1. a kind of calcium carbonate/hyaluronic acid combination drug carrier preparation method, which is characterized in that the pharmaceutical carrier is by kernel
It is formed with clad, the kernel is the porous nano calcium carbonate particle for loading insulin medicament, and the clad is repaired for folic acid
The hyaluronic acid of decorations；The preparation method comprises the following steps: 1) at room temperature, insulin medicament being dissolved in water, compound concentration is
The insulin medicament aqueous solution of 0.01~0.1mol/L, then by insulin medicament aqueous dispersion in containing surfactant
In oily phase, after stirring 30min, w/o type lotion is made；2) water-soluble Ca salt at room temperature, is dissolved in deionized water, prepares calcium ion
Concentration is the aqueous solution of 0.01~0.5mol/L；Water soluble carbonate is dissolved in deionized water, preparing carbon acid ion concentration is
The aqueous solution of 0.01~0.5mol/L；3) aqueous solution of calcium ion and carbanion is slowly instilled into the w/o type respectively
Lotion controls the micro excess of calcium ion, stirs 30min；4) hyaluronic acid aqueous solution is prepared, slowly by hyaluronic acid aqueous solution
Lotion made from step 3) is instilled, after stirring 30min, is centrifugated to get calcium carbonate/hyaluronic acid combination drug carrier is arrived.
2. calcium carbonate according to claim 1/hyaluronic acid combination drug carrier preparation method, which is characterized in that institute
Stating surfactant is w/o type, and concentration of the surfactant in oily phase is 0.05~2.0wt%, the surface-active
Sorbitan fatty ester, sorbitan monostearate, glycerin monostearate or citric acid fatty acid are selected in agent
One of glyceride is a variety of.
3. calcium carbonate according to claim 1/hyaluronic acid combination drug carrier preparation method, which is characterized in that institute
It states water-soluble Ca salt and selects one of calcium gluconate, calcium lactate, calcium chloride or calcium acetate or a variety of.
4. calcium carbonate according to claim 1/hyaluronic acid combination drug carrier preparation method, which is characterized in that institute
It states water soluble carbonate and selects the one or more of sodium carbonate, potassium carbonate or ammonium carbonate.
5. calcium carbonate according to claim 1/hyaluronic acid combination drug carrier preparation method, which is characterized in that institute
The concentration for stating hyaluronic acid aqueous solution is 0.05~2.0wt%.
6. calcium carbonate according to claim 1/hyaluronic acid combination drug carrier preparation method, which is characterized in that institute
State the hyaluronic acid that hyaluronic acid is modified with folic acid.
7. calcium carbonate according to claim 1/hyaluronic acid combination drug carrier preparation method, which is characterized in that institute
The partial size for stating Nano particles of calcium carbonate is 80~180nm.
8. calcium carbonate according to claim 1/hyaluronic acid combination drug carrier preparation method, which is characterized in that institute
State clad with a thickness of 15~35nm.
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| Title |
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| Crosslinked hyaluronic acid hydrogels: a strategy to functionalize and pattern;Tatiana Segura等;《Biomaterials》;20051231;第26卷;第359-371页 * |
| Dual targeting folate-conjugated hyaluronic acid polymeric micelles for paclitaxel delivery;Yanhua Liu等;《International Journal of Pharmaceutics》;20110916;第421卷;第160-169页 * |
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