EP0817619A1 - Nouvelles microspheres de poly-(lactide/glucolide) a liberation prolongee "sans eclatement" - Google Patents
Nouvelles microspheres de poly-(lactide/glucolide) a liberation prolongee "sans eclatement"Info
- Publication number
- EP0817619A1 EP0817619A1 EP96944247A EP96944247A EP0817619A1 EP 0817619 A1 EP0817619 A1 EP 0817619A1 EP 96944247 A EP96944247 A EP 96944247A EP 96944247 A EP96944247 A EP 96944247A EP 0817619 A1 EP0817619 A1 EP 0817619A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- microcapsules
- release
- uncapped
- emulsion
- capped
- 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.)
- Ceased
Links
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000013268 sustained release Methods 0.000 title abstract description 13
- 239000012730 sustained-release form Substances 0.000 title abstract description 13
- 239000003094 microcapsule Substances 0.000 claims abstract description 103
- 239000000203 mixture Substances 0.000 claims abstract description 70
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 66
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 48
- 229920001184 polypeptide Polymers 0.000 claims abstract description 47
- 239000013543 active substance Substances 0.000 claims abstract description 39
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims abstract description 36
- 229920001577 copolymer Polymers 0.000 claims abstract description 24
- 229920000642 polymer Polymers 0.000 claims description 92
- 238000000034 method Methods 0.000 claims description 32
- 108010019494 Histatins Proteins 0.000 claims description 29
- 102000006492 Histatins Human genes 0.000 claims description 28
- 239000004005 microsphere Substances 0.000 claims description 26
- 239000007762 w/o emulsion Substances 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 23
- 239000008346 aqueous phase Substances 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 239000000839 emulsion Substances 0.000 claims description 17
- 239000012071 phase Substances 0.000 claims description 17
- 238000005538 encapsulation Methods 0.000 claims description 14
- 238000013270 controlled release Methods 0.000 claims description 13
- 239000003995 emulsifying agent Substances 0.000 claims description 13
- 230000004071 biological effect Effects 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- 230000002459 sustained effect Effects 0.000 claims description 9
- 238000009472 formulation Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 230000001804 emulsifying effect Effects 0.000 claims description 7
- 239000005556 hormone Substances 0.000 claims description 7
- 229940088597 hormone Drugs 0.000 claims description 7
- 239000002736 nonionic surfactant Substances 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 239000003381 stabilizer Substances 0.000 claims description 7
- 238000009826 distribution Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 150000001413 amino acids Chemical class 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- -1 polyoxyethylene Polymers 0.000 claims description 5
- 230000007928 solubilization Effects 0.000 claims description 5
- 238000005063 solubilization Methods 0.000 claims description 5
- 230000000699 topical effect Effects 0.000 claims description 5
- 241000588724 Escherichia coli Species 0.000 claims description 4
- 229940035676 analgesics Drugs 0.000 claims description 4
- 230000000954 anitussive effect Effects 0.000 claims description 4
- 239000000730 antalgic agent Substances 0.000 claims description 4
- 239000003242 anti bacterial agent Substances 0.000 claims description 4
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 4
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 4
- 230000001754 anti-pyretic effect Effects 0.000 claims description 4
- 239000000043 antiallergic agent Substances 0.000 claims description 4
- 239000003416 antiarrhythmic agent Substances 0.000 claims description 4
- 229940088710 antibiotic agent Drugs 0.000 claims description 4
- 239000003146 anticoagulant agent Substances 0.000 claims description 4
- 229940127219 anticoagulant drug Drugs 0.000 claims description 4
- 239000000935 antidepressant agent Substances 0.000 claims description 4
- 229940005513 antidepressants Drugs 0.000 claims description 4
- 229940030600 antihypertensive agent Drugs 0.000 claims description 4
- 239000002220 antihypertensive agent Substances 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 239000002221 antipyretic Substances 0.000 claims description 4
- 229940125716 antipyretic agent Drugs 0.000 claims description 4
- 239000003434 antitussive agent Substances 0.000 claims description 4
- 229940124584 antitussives Drugs 0.000 claims description 4
- 239000003699 antiulcer agent Substances 0.000 claims description 4
- 230000000975 bioactive effect Effects 0.000 claims description 4
- 239000000496 cardiotonic agent Substances 0.000 claims description 4
- 230000003177 cardiotonic effect Effects 0.000 claims description 4
- 239000002934 diuretic Substances 0.000 claims description 4
- 229940030606 diuretics Drugs 0.000 claims description 4
- 230000000688 enterotoxigenic effect Effects 0.000 claims description 4
- 239000003172 expectorant agent Substances 0.000 claims description 4
- 230000003419 expectorant effect Effects 0.000 claims description 4
- 229940066493 expectorants Drugs 0.000 claims description 4
- 238000007918 intramuscular administration Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229940035363 muscle relaxants Drugs 0.000 claims description 4
- 239000003158 myorelaxant agent Substances 0.000 claims description 4
- 239000000902 placebo Substances 0.000 claims description 4
- 229940068196 placebo Drugs 0.000 claims description 4
- 239000000932 sedative agent Substances 0.000 claims description 4
- 229940125723 sedative agent Drugs 0.000 claims description 4
- 230000000087 stabilizing effect Effects 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000007920 subcutaneous administration Methods 0.000 claims description 4
- 229940124549 vasodilator Drugs 0.000 claims description 4
- 239000003071 vasodilator agent Substances 0.000 claims description 4
- 239000008307 w/o/w-emulsion Substances 0.000 claims description 4
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 3
- 230000003556 anti-epileptic effect Effects 0.000 claims description 3
- 239000001961 anticonvulsive agent Substances 0.000 claims description 3
- 229960003965 antiepileptics Drugs 0.000 claims description 3
- 229920001400 block copolymer Polymers 0.000 claims description 3
- 229920001983 poloxamer Polymers 0.000 claims description 3
- 239000003488 releasing hormone Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 101710082795 30S ribosomal protein S17, chloroplastic Proteins 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 2
- 239000000275 Adrenocorticotropic Hormone Substances 0.000 claims description 2
- 102000055006 Calcitonin Human genes 0.000 claims description 2
- 108060001064 Calcitonin Proteins 0.000 claims description 2
- 102400000739 Corticotropin Human genes 0.000 claims description 2
- 101800000414 Corticotropin Proteins 0.000 claims description 2
- 150000008574 D-amino acids Chemical class 0.000 claims description 2
- 102400001368 Epidermal growth factor Human genes 0.000 claims description 2
- 101800003838 Epidermal growth factor Proteins 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 2
- 239000000427 antigen Substances 0.000 claims description 2
- 102000036639 antigens Human genes 0.000 claims description 2
- 108091007433 antigens Proteins 0.000 claims description 2
- 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 2
- 229960004015 calcitonin Drugs 0.000 claims description 2
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](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](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 claims description 2
- 229960000258 corticotropin Drugs 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- 239000000147 enterotoxin Substances 0.000 claims description 2
- 231100000655 enterotoxin Toxicity 0.000 claims description 2
- 229940116977 epidermal growth factor Drugs 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- 230000003053 immunization Effects 0.000 claims description 2
- 238000002649 immunization Methods 0.000 claims description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 2
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 claims description 2
- 229920000053 polysorbate 80 Polymers 0.000 claims description 2
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 claims description 2
- 229960005486 vaccine Drugs 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 3
- 239000011159 matrix material Substances 0.000 abstract 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 23
- 230000001186 cumulative effect Effects 0.000 description 18
- 239000000654 additive Substances 0.000 description 10
- 238000004945 emulsification Methods 0.000 description 7
- 230000000996 additive effect Effects 0.000 description 5
- 238000001878 scanning electron micrograph Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 239000000945 filler Substances 0.000 description 4
- 230000006641 stabilisation Effects 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical class OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 description 3
- 229920002988 biodegradable polymer Polymers 0.000 description 3
- 239000004621 biodegradable polymer Substances 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000011105 stabilization Methods 0.000 description 3
- 102000009027 Albumins Human genes 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 239000001814 pectin Substances 0.000 description 2
- 235000010987 pectin Nutrition 0.000 description 2
- 229920001277 pectin Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical compound C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000008393 encapsulating agent Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 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
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- This invention relates to providing novel biocompatible and biodegradable microspheres for burst-free programmable sustained release of biologically active agents, inclusive of polypeptides, over a period of up to 100 days in an aqueous physiological environment.
- PLGA poly(lactide/glycolides)
- L/G lactide/glycolide
- Further prior art preparations of PLGA utilized fillers or additives in the inner aqueous layer to improve the stability and encapsulation efficency and/or to increase the viscosity of the aqueous layer, thereby modulating polymer hydrolysis and the biologically active agent or polypeptide release.
- PLGA copoly ers were end-capped, in that the terminal carboxyl end groups were blocked.
- the icrocapsule preparations exhibited a low to moderate burst release of - 10-40% of the entrapped polypeptide in the first 24 hours after placement in an aqueous physiological environment. In part, these characteristics are due to the use of fillers in the inner aqueous phase. Further, a 1-month release of polypeptide is known with the use of a 75/25 co-polymer of PLGA of Mw * ⁇ 20,000.
- This invention provides biocompatible and biodegradable microspheres that have been designed for novel, burst free, programmable sustained release of biologically active agents, including polypeptides over a period of up to 100 days in an aqueous physiological environment.
- burst-free, programmable sustained release is achieved through the use of a unique blend of the *uncapped' and end-capped forms of poly(lactide/glycolide) polymer in the molecular weight range of 2,000 to 60,000 daltons.
- microspheres described in this invention are produced by a unique emulsification technique wherein an inner water-in-oil (w/o) emulsion is stabilized by dispersing in a solvent-saturated aqueous phase containing an emulsion stabilizer. A ternary w/o/w emulsion is then formed by emulsifying the above w/o emulsions in an external pre-coo ed aqueous phase containing an o/w emulsifier.
- w/o water-in-oil
- a ternary w/o/w emulsion is then formed by emulsifying the above w/o emulsions in an external pre-coo ed aqueous phase containing an o/w emulsifier.
- the inner w/o emulsion is comprised of an aqueous layer containing from - 2 to about 20% (w/w) of the active agent to be entrapped and an oil layer containing poly(lactide/glycolide) copolymer in concentrations ranging from - 5 to about— 50% (w/w oil phase) .
- the copolymer includes molecular weight ranging from 2,000 to about 60,000 daltons, with molar composition of lactide/glycolide from 90/10 to 40/60 and a blend of its uncapped and end-capped forms in a ratio of 100/0 to 1/99. Very high encapsulation efficiencies of about 80 to 100% are achieved depending on polymer molecular weight and structural form.
- Programmable release of active core over variable durations between 1-100 days is achieved by a judicious selection of process parameters such as polymer concentration, peptide concentration and the aqueous/oil phase ratio.
- This invention is particularly suitable for high encapsulation efficiencies and burst-free, continuous programmable release of polypeptides of molecular weights ranging from 1,000 to about 250,000 daltons, and also other biologically active agents over a period of 1-100 days.
- a uniqueness of the invention is that when using a 100/0 blend of the uncapped and capped polymer, the final phase of active core release is concurrent with the complete solubilization of the polymer to innocuous components, such as lactic and glycolic acids. This is a significant advantage over the currently available 30 day - release systems wherein a major regulatory concern is about toxicity of residual polymer at the site of administration, long after release of the active core.
- microcapsules described in this invention are suitable for administration via several routes such as parenteral
- FIG. 1 shows a comparison of drug release from a conventional system versus a controlled release system. Peak and valley levels from conventional administrations are shown, in contrast to the steady therapeutic levels from the controlled release administration.
- FIG. 2 shows a scanning electron micrograph of PLGA microspheres prepared by the process described in the invention using 50/50 uncapped polymer of Mw 8-12k dalton and shows superior sphere morphology, sphere integrity, and narrow size distribution.
- FIG. 2a shows a scanning electron micrograph of PLGA microspheres prepared by conventional solvent evaporation method using a 50/50 12k uncapped polymer of Mw 8-12k dalton.
- FIG. 3 shows cumulative Histatin release from PLGA microspheres, wherein release profiles from several batches are prepared using 50/50, uncapped polymer (of Mw 8-l2k dalton) and wherein the process parameters are varied to modulate release between 1 and 35 days.
- FIG. 4 shows a scanning electron micrograph of solid, smooth spherical surfaces of PLGA microspheres prepared by the method of in the invention using 50/50, end-capped polymer (of Mw 30-40k dalton) .
- FIG. 5 shows cumulative Histatin release from PLGA microspheres, wherein the release profiles are from several batches prepared using 50/50, uncapped and end-capped polymer of Mw 30-4Ok daltons, and wherein the process parameters are varied to modulate release between 28 to 60 days.
- FIG. 6 shows cumulative Histatin release from PLGA microspheres, wherein combined release profiles from several batches have been prepare ⁇ using 50/50, uncapped and end-capped polymer of Mw 8-40k daltons, while varying the process parameters to modulate release between 1 and 60 days.
- FIG. 7 shows a cumulative percent release of LHRH from PLGA microspheres prepared using uncapped polymer of Mw 8-12 daltons.
- This invention relates to the design of biocompatible and biodegradable microspheres for novel, programmable sustained release of biologically active agents, including polypeptides over a period of up to 100 days in an aqueous physiological environment with little or no burst release.
- this invention achieves high encapsulation efficiency and *burst-free' release without the use of any additive.
- burst-free, programmable sustained release is achieved through the use of a unique blend of the 'uncapped' and end- capped forms of poly (lactide/glycolide) polymer.
- the 'uncapped' form refers to "poly(lactide/glycolide) with free carboxyl end groups" which renders the polymer more hydrophilic compared to the routinely used end-capped form.
- Currently used 'end-capped' polymer hydrates between 4-12 weeks depending on the molecular weight, resulting in an intermediate 'no release' or a 'lag phase'.
- the uncapped polymer hydrates typically between 5 to 60 days depending on the molecular weight, thus releasing its core continuously without a lag phase.
- a careful blend of the two forms and appropriate molecular weights and L/G ratios results in a continuous release between 1 to 100 days.
- release within this time is programmable by a judicious selection of process parameters such as polymer concentration, peptide concentration and the aqueous/oil phase ratio.
- the coploymer in this invention includes molecular weight ranging from 2,000 to 60,000 daltons, a lactide/glycolide ratio of 90/10 to 40/60 and a blend of the uncapped/capped forms in the ratio of 100/0 to 1/99.
- the molecular weight of the polypeptide may be in the range of 1000 to 250,000 daltons while that of other biologically active agents may range from 100 to 100,000 daltons.
- Microcapsules described in this invention are prepared by a unique aqueous emulsification techinique which has been developed for use with the uncapped polymer to provide superior sphere morphology, sphere integrity and narrow size distribution. This is accomplished by first preparing an inner water-in-oil (w/o) by mixing the solutions of polymer in an organic solvent such as methylene chloride and the biologically active agent in water.
- an organic solvent such as methylene chloride
- a ternary emulsion is then formed by emulsifying the w/o emulsion in an external aqueous phase containing the same emulsifier as above at concentrations ranging from 0.25 - 1% w/v.
- Microcapsules are hardened upon solvent removal by evaporation, rinsed to remove residual emulsifier and lyophilized. Low temperature is used both at the time of primary emulsification (w/o emulsion formation) and during the formation of the final w/o/w emulsion to achieve stable emulsion and superior sphere characteristics.
- a biologically active agent is any water-soluble hormone drugs, antibiotics, antitumor agents, antiinflammatory agents, antipyretics, analgesics, antitussives, expectorants, sedatives, muscle relaxants, antiepileptics, antiulcer agents, antidepressants, antiallergic drugs, cardiotonics, antiarrhythmic drugs, vasodilators, antihypertensives, diuretics, anticoagulants, antinarcotics, etc. More precisely, applicants have discovered a pharmaceutical composition and process with the following itemized features:
- biodegradable poly(lactide/glycolide) is a blend of uncapped and capped forms, in ratios ranging from 100/0 to 1/99.
- L/G ratio for uncapped and end-capped polymer is 90/10 to 40/60. 5.
- microcapsules of item 6 wherein said polypeptide is histatin consisting of 12 amino acids and having a molecular weight of 1563.
- the microcapsules of items 1 or 2 or 3 or 4 or 5 or 6 characterized by the capacity to completely release histatin in an aqueous physiological environment from 1-35 days with a 100/0 blend of uncapped and end-capped poly(lactide/glycolide) having a
- microcapsules of items 1 or 2 or 3 or 4 or 5 or 6 characterized by the capacity to completely release histatin in an aqueous physiological environment from 18-40 days with a 100/0 blend of uncapped and end-capped poly(lactide/glycolide) having a
- microcapsules of items 1 or 2 or 3 or 4 or 5 or 6 characterized by the capacity to release up to 90% of the histatin in an aqueous physiological environment from 28-70 days with a 0/100 blend of uncapped and end-capped poly(lactide/glycolide) having a L/G ratio of 48/52 to 52/48 and a molecular weight range of 10,000-40,000 daltons.
- microcapsules of items 1 or 2 or 3 or 4 or 5 or 6 characterized by the capacity to release up to 80% of histatin in an aqueous physiological environment from 56-100 days with a 0/100 blend of uncapped and end-capped poly(lactide/glycolide) having a L/G ratio of 75/25 and a molecular weight of ⁇ 15,000 daltons.
- microcapsules of items 7 or 8 or 9 or 10 or 11 having analogs of histatin with chain lengths of from 11-24 amino acids of molecular weights from 1,500-3,000 daltons and characterized by the following structures:
- microcapsules of items 1 or 2 or 3 or 4 or 5 wherein the biologically active agent is a polypeptide Leutinizing hormone releasing hormone (LHRH) that is a decapeptide of molecular weight 1182 in its acetate form, and having the structure: p- E H W S Y G L R P G
- microcapsule of items 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 having a molecular weight of from 1,000 to 250,000 daltons.
- microcapsules of items 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 wherein release of profiles of variable rates and duration are achieved by blending uncapped and capped polymer in different ratios within the same microshreres.
- ETEC such as CFA/I,CFA/II,CS1,CS3,CS6 and CS17 and other ETEC- related enterotoxins.
- microcapsules of items 1 or 2 or 3 or 4 or 5 wherein said biologically active agents are selected from the group consisting of water-soluble hormone drugs, antibiotics, antitumor agents, anti inflammatory agents, antipyretics, analgesics, antitussives, expectorants, sedatives, muscle relaxants, antiepileptic ⁇ , antiulcer agents, antidepressants, antiallergic drugs, cardiotonics, antiarrhythmic drugs, vasodilators, antihypertensives, diuretics, anticoagulants, and antinarcotics, in the molecular weight range of 100-100,000 daltons.
- said biologically active agents are selected from the group consisting of water-soluble hormone drugs, antibiotics, antitumor agents, anti inflammatory agents, antipyretics, analgesics, antitussives, expectorants, sedatives, muscle relaxants, antiepileptic ⁇ , antiulcer agents, antidepressants, antiallergic drugs, cardiotonics, antiarrhythm
- microcapsules of items 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 wherein said biodegradable poly(lactide/glycolide) is in an oil phase, and is present in about 1-50% (w/w).
- a process for preparing controlled release microcapsule formulations characterized by burst-free, sustained, programmable release of biologically active agents comprising: Dissolving biodegradable poly (lactide/glycolide) , in uncapped form in methylene chloride, and dissolving a biologically active agent or active core in water; adding the aqueous layer to the polymer solution and emulsifying to provide an inner water-in-oil (w/o) emulsion; stabilizing the w/o emulsion in a solvent-saturated aqueous phase containing a oil-in-water (o/w) emulsifier; adding said w/o emulsion to an external aqueous layer containing oil-in- water emulsifier to form a ternary emulsion; and stirring the resulting water-in-oil-in-water (w/o/w) emulsion for sufficient time to remove said solvent, and rinsing hardened microcapsules with
- a process for preparing controlled release microcapsule formulations characterized by burst-free, sustained, programmable release of biologically active agents comprising: dissolving biodegradable poly(lactide/glycolide) in end- capped form in methylene chloride, and dissolving a biologically active agent or active core in water; adding the aqueous layer to the polymer solution and emulsifying to provide an inner water- in-oil emulsion; stabilizing the w/o emulsion in a solvent- saturated aqueous phase containing a oil-in-water (o/w) emulsifier; adding said w/o emulsion to an external aqueous layer containing oil-in-water emulsifier to form a ternary emulsion; and stirring a resulting water-in-oil-water (w/o/w) emulsion for sufficient time to remove said solvent; and rinsing hardened microcapsules with water; and lyophilizing said
- microcapsules of items 6 or 7 or 8 or 9 or 10 or 11 wherein, when entrapped polypeptide such as histatin is inactive at a low pH, a non-ionic surfactant such as polyoxyethylene sorbitan fatty acid esters (Tween 80, Tween 60 and Tween 20) and polyoxyethylene - polyoxypropylene block copolymers (Pluronics) is added to the inner aqueous phase to maintain biological activity of the released polypeptide.
- a non-ionic surfactant such as polyoxyethylene sorbitan fatty acid esters (Tween 80, Tween 60 and Tween 20) and polyoxyethylene - polyoxypropylene block copolymers (Pluronics) is added to the inner aqueous phase to maintain biological activity of the released polypeptide.
- microcapsules of item 30 wherein placebo spheres loaded with non-ionic surfactant are coadministered with polypeptide-loaded spheres to maintain biological activity of the released peptide where the addition of non-ionic surfactants in the inner aqueous phase is undesirable for successful encapsulation of the acid pH sensitive polypeptide.
- microcapsules of items 1 or 2 or 3 or 4 or 5 or 6 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 comprising a blend of uncapped and capped polymer, wherein complete solubilization of the copolymer leaves no residual polymer at the site of administration and occurs concurrently with the complete release of the entrapped agent.
- Ease of administration of the microcapsules in various dosage forms via several routes such as parenteral (intramuscular and sucutaneous), oral, topical, nasal, vaginal, etc.
- hydrophilic homo-and co-polymers based on D,L-lactide and glycolide contains hydrophilic adjusted homo-and co-polymers with free carboxylic end groups, and is characterized by the formula :
- FIG. 1 depicts a blood-drug concentration versus time graph that shows conventional drug administration using a series of dosages compared to an ideal controlled release system.
- drugs have a therapeutic range, above which they are toxic and below which they are ineffective. Oscillating drug levels that are commonly observed following systemic administration causes alternating periods of ineffectiveness and toxicity.
- a sustained-release encapsulated biologically active agent or polypeptide preparation ideally, will maintain the drug in the desired therapeutic range by means of a single dose, as depicted in the
- FIG.l THERAPEUTIC RANGE in FIG.l , where the ideal case for controlled release is shown.
- FIG. 2 there is shown a scanning electron micrograph of PLGA microspheres prepared using 50/50 uncapped polymer of Mw 8- 12k dalton. The uncapped polymer has solid, smooth spherical surfaces, and is suited to provide a "burst free" release system.
- Table I is a summarization of the microsphere process description for preparing a peptide system (Histatin peptide) having a controlled release over the course of from l to 100 days.
- Release profiles can be modified by a judicious blend of uncapped and capped polymers either in separate microspheres or in the same microspheres. Release from microcapsule formulations 1 through 21 listed in Table 1, occur independently of each other and hence the cumulative release from blends of these formulations are additive. By blending several formulations of uncapped and end-capped microspheres, release curves of any desired duration can be tailored. In addition, based on the release characteristics of uncapped and end-capped polymers. blending of the two forms in a single formulation comprising different ratios of uncapped to capped polymer, would significantly influence the polymer hydration and hence release of the active core thereby providing release curves of any desirable pattern. Manipulation of polymer hydration and degradation resulting in modulation of release of active core is achieved by the addition of uncapped polymer to end-capped polymer in amounts as low as 1% up to 100%.
- FIG. 4 a view is provided through a scanning electron micrograph of PLGA microspheres designed for a one to two month release system prepared using end-capped polymer of Mw 30- 0k daltons.
- FIG. 5 depicts the cumulative Histatin release from PLGA microspheres, in which the release profiles are from several batches prepared using 50/50, uncapped and capped polymer, and varying the process parameters to modulate release between 28 to 60 days.
- Figure 6 represents cumulative Histatin release from PLGA microspheres these combined release profiles are from several batches prepared using 50/50 uncapped and capped polymer, and varying the process parameters to modulate release between 1-60 days.
- a biologically active agent is any water-soluble antibiotics, antitumor agents, antipyretics analgesics, anti-inflammatory agents, antitussives, expectorants, sedatives, muscle relaxants, anti epileptics, antiulcer agents, anti-depressants, anti-allergic drugs, cardiotonics, antiarrhythmics drugs, vasodilators, antihypertensives, diuretics, anticoagulants, hormone drugs, anti-narcotics, etc.
- burst free sustained release delivery of biologically active agents from PLGA microshperes is accomplished in the context of this invention using of 90/10 to 40/60 molar ratios, and ratios of uncapped polymer to end-capped polymer of 100/0 to 1/99.
- Peptide loads - from 2 to about 40% (w/w polymer) and by using the unique aqueous emulsification method described in the invention.
- Ease of administration of the microcapsules in various dosages forms via several routes such as parenteral (intramusclar and subcutaneous), oral, topical, nasal, vaginal, etc.
- Polylactide/glycolide (PLGA) microcapsules are prepared by a unique aqueous emulsification technique which has been developed for use with the uncapped polymer to provide superior sphere morphology, sphere integrity and narrow size distribution (See Figures la and lb) . This is accomplished by dissolving the polymer in a chlorinated hydrocarbon solvent such as methylene chloride and dissolving the biologically active agent in water. A w/o emulsion is then formed by mixing the solutions of polymer and the active agent by sonication, followed by emulsion stabilization in a solvent - saturated aqueous solution containing polyvinyl alcohol.
- a chlorinated hydrocarbon solvent such as methylene chloride
- a ternary emulsion is then formed by emulsifying the w/o emulsion in an external, pre-cooled aqueous phase containing polyvinyl alcohol (0.25 - 1% w/v) .
- Microcapsules are hardened upon removal of solvent by evaporation, rinsed to remove any residual emulsifier, and then lyophilized.
- Table 1 lists the microcapsule compositions, Nos. 1-21 thus prepared, consisting of a biologically active polypeptide, Histatin (composed of 12 amino acids and a molecular weight of 1563) and blends of uncapped and capped polymer of ratios 100/0 to 1/99, and having a lactide/glycolide ratio of 90/10 to 40/60, and a molecular weight range between 2000 to 60,000 daltons.
- Example 2
- Microcapsule compositions are prepared as described in Example 1 wherein the copolymer L/G ratio is 48/52 to 52/48, and the ratio of uncapped/capped polymer is 100/0.
- the active core is Histatin (Mw 1563), the polymer molecular weight is ⁇ 15,000 and the polymer concentrations vary from 7% to - 40% w/w.
- Compositions 1,2,4 12-14 and 16-18 are listed in Table 1.
- Release profiles of the active core from the compositions in an aqueous physiological environment are plotted as cumulative percentage release versus time, and presented in Figure 2.
- Burst-free, variable release from 1-35 days is achieved by varying the polymer concentration from 7 to - 40% w/w in the oil phase.
- Microcapsule compositions are prepared as described in Example 2, wherein the aqueous /oil ratio is varied from 1/4 to 1/20 (v/v) .
- Compositions 1,2,4 and 12 are listed in Table 1.
- Release profiles of the active core from the compositions in an aqueous physiological environment described in Example 2 are plotted as cumulative percentage release versus time, and presented in Figure 2.
- Burst-free, continuous release from 1-35 days, with different onset and completion times are achieved by selecting different w/o ratios in the inner core.
- Example 4 Microcapsule compositions are prepared as described in
- Example 2 wherein the polymer molecular weight is 28,000-40,000 and polymer concentrations vary from 5% to - 15% w/w.
- Compositions 19-21 are listed in Table 1. Release profiles of the active core from the compositions in an aqueous physiological environment are described in Example 2 are plotted as cumulative percentage release versus time and presented in Figure 3. Burst-free, variable release from 18-40 days is achieved by varying the polymer concentration.
- Example 5 Microcapsule compositions are prepared as described in
- Example 2 wherein the ratio of uncapped/capped polymer is 1/99 and polymer concentrations vary between 5% to - 12% w/w.
- Compositions 10 and 11 are listed in Table 1. Release profiles of the active core from the compositions in an aqueous physiological environment are described in Example 2, and plotted as cumulative percentage release versus time and presented in Figure 2. Burst-free, variable release from 28-70 days is achieved by varying the polymer concentration in the oil phase.
- Example 6 Microcapsule compositions are prepared as described in
- Example 5 wherein polymer molecular weight is 28,000-40,000 and polymer concentrations vary between 5% to - 12% w/w.
- Compositions 5 and 6 are listed in Table 1. Release profiles of the active core from the compositions in an aqueous physiological environment are described in Example 2 and are plotted as cumulative percentage release versus time, and presented in Figure 3. Burst-free, variable release from 28-70 days is achieved by varying the polymer concentration.
- Microcapsule compositions are prepared as described in Example 6, wherein the aqueous/oil ratio varies between 1/5 to 1/25 (v/v) .
- Compositions 3 and 7 are listed in Table 1.
- Burst-free, variable release from 28-70 days is achieved by varying the aqueous/oil ratios.
- Microcapsule compositions are prepared as described in Example 5, wherein the copolymer ratio is 75/25 and polymer concentrations vary between 5% to - 25% w/w.
- Compositions 8 and 9 are listed in Table 1.
- Release profiles of the active core from the compositions in an aqueous physiological environment are described in Example 2, and are plotted as cumulative percentage release versus time, and presented in Figure 2.
- Burst-free, variable release from 56- 90 days is achieved by varying the polymer concentration in the oil phase.
- Microcapsule compositions are described in Example 2, wherein the active core is leutinizing hormone releasing hormone (LHRH, a decapeptide of molecular weight 1182) and the polymer concentration is -40% w/w. Release profiles of the active core from the composition in an aqueous physiological environment is described in Example 2, and is plotted as cumulative percentage release versus time, and presented in Figure 4.
- LHRH leutinizing hormone releasing hormone
- Burst-free, continuous and complete release is achieved within 35 days, similar to Histatin acetate.
- Microcapsule compositions are prepared as described in Example 2, wherein an additive such as sodium salt (carbonate or bicarbonate) is added to the inner aqueous phase at concentrations of 1-10% w/w to maintain the biological activity of the released polypeptide.
- an additive such as sodium salt (carbonate or bicarbonate) is added to the inner aqueous phase at concentrations of 1-10% w/w to maintain the biological activity of the released polypeptide.
- Microcapsule compositions are prepared as described in Example 2, wherein an additive such as a nonionic surfactant, polyoxyethylene/polyoxypropylene block copolymer (Pluronics F68 and F127) is added to either the inner oil or the aqueous phase at concentrations from 10-100% w/w, to maintain the biological activity of the released polypeptide.
- an additive such as a nonionic surfactant, polyoxyethylene/polyoxypropylene block copolymer (Pluronics F68 and F127) is added to either the inner oil or the aqueous phase at concentrations from 10-100% w/w, to maintain the biological activity of the released polypeptide.
- Burst-free, continuous release from 1-35 days is achieved similar to Examples 2 * 3, and the released polypeptide is bioactive due to the presence of the surfactant.
- Cumulative histatin release from the microcapsule compositions described in Examples 1 through 11 and release profiles plotted in Figures 2 and 3 show the burst-free, programmable peptide release for variable duration from 1-100 days. Virtually any pattern of cumulative release is achievable over ' a 100 day duration by a judicious blending of several compositions, as shown in these figures.
Abstract
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US59097396A | 1996-01-24 | 1996-01-24 | |
US590973 | 1996-01-24 | ||
PCT/US1996/019440 WO1997026869A1 (fr) | 1996-01-24 | 1996-11-18 | Nouvelles microspheres de poly-(lactide/glucolide) a liberation prolongee 'sans eclatement' |
CNB961947683A CN100391445C (zh) | 1996-01-24 | 1996-11-18 | 新型的“非突发的”持续释放聚(丙交酯/乙交酯)的微球 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0817619A1 true EP0817619A1 (fr) | 1998-01-14 |
EP0817619A4 EP0817619A4 (fr) | 1999-02-03 |
Family
ID=25744089
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP96944247A Ceased EP0817619A4 (fr) | 1996-01-24 | 1996-11-18 | Nouvelles microspheres de poly-(lactide/glucolide) a liberation prolongee "sans eclatement" |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP0817619A4 (fr) |
JP (1) | JPH11509862A (fr) |
CN (1) | CN100391445C (fr) |
AP (1) | AP665A (fr) |
AU (1) | AU722884B2 (fr) |
BR (1) | BR9607752B1 (fr) |
NZ (1) | NZ325561A (fr) |
WO (1) | WO1997026869A1 (fr) |
Families Citing this family (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7033608B1 (en) * | 1995-05-22 | 2006-04-25 | The United States Of America As Represented By The Secretary Of The Army | “Burst-free” sustained release poly-(lactide/glycolide) microspheres |
TW577759B (en) | 1997-04-18 | 2004-03-01 | Ipsen Pharma Biotech | Sustained release compositions in the form of microcapsules or implants and the process for their preparation |
CN1075945C (zh) * | 1998-02-26 | 2001-12-12 | 中国科学院化学研究所 | 一种高分子包囊胰岛素微粒体及其制备方法和用途 |
CN1073412C (zh) * | 1998-03-19 | 2001-10-24 | 中国科学院化学研究所 | 一种高分子微包囊的制备方法 |
US7217770B2 (en) * | 2000-05-17 | 2007-05-15 | Samyang Corporation | Stable polymeric micelle-type drug composition and method for the preparation thereof |
US6726918B1 (en) | 2000-07-05 | 2004-04-27 | Oculex Pharmaceuticals, Inc. | Methods for treating inflammation-mediated conditions of the eye |
DE60114229T2 (de) | 2000-11-29 | 2006-07-06 | Allergan, Inc., Irvine | Verhinderung von transplantatabstossung im auge |
US20040137059A1 (en) * | 2003-01-09 | 2004-07-15 | Thierry Nivaggioli | Biodegradable ocular implant |
US20050048099A1 (en) | 2003-01-09 | 2005-03-03 | Allergan, Inc. | Ocular implant made by a double extrusion process |
US7993634B2 (en) | 2004-04-30 | 2011-08-09 | Allergan, Inc. | Oil-in-oil emulsified polymeric implants containing a hypotensive lipid and related methods |
US7799336B2 (en) | 2004-04-30 | 2010-09-21 | Allergan, Inc. | Hypotensive lipid-containing biodegradable intraocular implants and related methods |
US9498457B2 (en) | 2004-04-30 | 2016-11-22 | Allergan, Inc. | Hypotensive prostamide-containing biodegradable intraocular implants and related implants |
US20050244469A1 (en) | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Extended therapeutic effect ocular implant treatments |
US8722097B2 (en) | 2004-04-30 | 2014-05-13 | Allergan, Inc. | Oil-in-water method for making polymeric implants containing a hypotensive lipid |
GB0517674D0 (en) * | 2005-08-31 | 2005-10-05 | Astrazeneca Ab | Formulation |
GB0517673D0 (en) * | 2005-08-31 | 2005-10-05 | Astrazeneca Ab | Formulation |
CN101007169B (zh) * | 2006-01-23 | 2011-05-25 | 珠海市嘉族生物科技有限公司 | 一种鸡卵黄免疫球蛋白微胶囊及其制备方法和应用 |
KR100816065B1 (ko) | 2006-11-27 | 2008-03-24 | 동국제약 주식회사 | 초기 방출억제 특성이 우수한 서방출성 마이크로캡슐의제조방법 및 이에 의해 제조되는 마이크로캡슐 |
US8956641B2 (en) * | 2008-04-18 | 2015-02-17 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for treatment of inflammatory diseases |
US8889173B2 (en) * | 2008-04-18 | 2014-11-18 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for treatment of pain and/or inflammation |
CN101612111B (zh) * | 2008-06-24 | 2011-11-23 | 上海医药工业研究院 | 醋酸诺美孕酮或其类似物的缓释微球及其制备方法和用途 |
KR20100037389A (ko) * | 2008-10-01 | 2010-04-09 | 연세대학교 산학협력단 | 다중 약물방출조절이 가능한 솔리드 마이크로구조체 및 이의 제조방법 |
USRE49251E1 (en) | 2010-01-04 | 2022-10-18 | Mapi Pharma Ltd. | Depot systems comprising glatiramer or pharmacologically acceptable salt thereof |
CN102357080B (zh) * | 2011-11-04 | 2014-07-16 | 无锡中科光远生物材料有限公司 | 一种酸性环境中可实现药物快速释放的智能型多功能空心微球及其制备方法 |
US10675376B2 (en) * | 2012-05-24 | 2020-06-09 | Ethicon Llc | Mechanically strong absorbable polymeric blend compositions of precisely controllable absorption rates, processing methods, and products therefrom |
HUE036141T2 (hu) * | 2013-06-20 | 2018-06-28 | Pharmathen Sa | Szigmoid kibocsátási profillal bíró polilaktid-poliglikolid mikrorészecskék elõállítása |
US20170022256A1 (en) * | 2015-07-23 | 2017-01-26 | General Biologicals Corporation | Anti-fungal and anti-bacterial peptide and therapeutic method using same |
CN110382052A (zh) | 2017-03-26 | 2019-10-25 | Mapi医药公司 | 用于治疗进展型形式的多发性硬化症的格拉替雷储库系统 |
CN113384536B (zh) * | 2020-03-14 | 2024-04-02 | 鲁南制药集团股份有限公司 | 一种注射用双羟萘酸加兰他敏缓释微粒及其制备方法 |
CN115025290A (zh) * | 2022-06-15 | 2022-09-09 | 浙江天妍生物科技有限公司 | 一种可降解微球及其生产工艺 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0052510B1 (fr) * | 1980-11-18 | 1986-08-27 | Syntex (U.S.A.) Inc. | Microencapsulation de polypeptides hydrosolubles |
DE4005415A1 (de) * | 1990-02-21 | 1991-08-22 | Boehringer Ingelheim Kg | Verfahren zur herstellung von polyestern auf der basis von hydroxycarbonsaeuren |
EP0463194A1 (fr) * | 1990-06-23 | 1992-01-02 | Boehringer Ingelheim Kg | Procédé pour la préparation de poly(DL-lactide) et son utilisation comme support d'agents thérapeutiques |
DE4235312A1 (de) * | 1991-10-23 | 1993-04-29 | Boehringer Ingelheim Kg | Halbfeste mischungen aus oligomeren und/oder polymeren auf der basis von milchsaeure, verfahren zu deren herstellung und deren verwendung als resorbierbare implantate |
US5410016A (en) * | 1990-10-15 | 1995-04-25 | Board Of Regents, The University Of Texas System | Photopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers |
DE19513659A1 (de) * | 1995-03-10 | 1996-09-12 | Boehringer Mannheim Gmbh | Polypeptid-enthaltende pharmazeutische Darreichungsformen in Form von Mikropartikeln und Verfahren zu deren Herstellung |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4622244A (en) * | 1979-09-04 | 1986-11-11 | The Washington University | Process for preparation of microcapsules |
US4623588A (en) * | 1984-02-06 | 1986-11-18 | Biotek, Inc. | Controlled release composite core coated microparticles |
DK0724431T3 (da) * | 1993-10-22 | 2003-01-06 | Genentech Inc | Fremgangsmåder og sammensætninger til mikroindkapsling af adjuvanser |
GB9412273D0 (en) * | 1994-06-18 | 1994-08-10 | Univ Nottingham | Administration means |
-
1996
- 1996-11-18 EP EP96944247A patent/EP0817619A4/fr not_active Ceased
- 1996-11-18 NZ NZ325561A patent/NZ325561A/xx not_active IP Right Cessation
- 1996-11-18 AU AU14104/97A patent/AU722884B2/en not_active Ceased
- 1996-11-18 JP JP9526833A patent/JPH11509862A/ja active Pending
- 1996-11-18 AP APAP/P/1997/001088A patent/AP665A/en active
- 1996-11-18 CN CNB961947683A patent/CN100391445C/zh not_active Expired - Fee Related
- 1996-11-18 WO PCT/US1996/019440 patent/WO1997026869A1/fr not_active Application Discontinuation
- 1996-11-18 BR BRPI9607752-2A patent/BR9607752B1/pt not_active IP Right Cessation
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0052510B1 (fr) * | 1980-11-18 | 1986-08-27 | Syntex (U.S.A.) Inc. | Microencapsulation de polypeptides hydrosolubles |
DE4005415A1 (de) * | 1990-02-21 | 1991-08-22 | Boehringer Ingelheim Kg | Verfahren zur herstellung von polyestern auf der basis von hydroxycarbonsaeuren |
EP0463194A1 (fr) * | 1990-06-23 | 1992-01-02 | Boehringer Ingelheim Kg | Procédé pour la préparation de poly(DL-lactide) et son utilisation comme support d'agents thérapeutiques |
US5410016A (en) * | 1990-10-15 | 1995-04-25 | Board Of Regents, The University Of Texas System | Photopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers |
DE4235312A1 (de) * | 1991-10-23 | 1993-04-29 | Boehringer Ingelheim Kg | Halbfeste mischungen aus oligomeren und/oder polymeren auf der basis von milchsaeure, verfahren zu deren herstellung und deren verwendung als resorbierbare implantate |
DE19513659A1 (de) * | 1995-03-10 | 1996-09-12 | Boehringer Mannheim Gmbh | Polypeptid-enthaltende pharmazeutische Darreichungsformen in Form von Mikropartikeln und Verfahren zu deren Herstellung |
Non-Patent Citations (2)
Title |
---|
R. JEYANTHI ET AL.: "NOVEL BURST FREE PROGRAMMABLE BIODEGRADABLE MICROSPHERES FOR CONTROLLED RELEASE OF POLYPEPTIDES" PROC. INT. SYMP. CONTROL. RELEASE BIOACT. MATER. (1996),July 1996, pages 351-352, XP002086331 KYOTO * |
See also references of WO9726869A1 * |
Also Published As
Publication number | Publication date |
---|---|
BR9607752B1 (pt) | 2009-05-05 |
CN1188408A (zh) | 1998-07-22 |
AP665A (en) | 1998-08-19 |
AP9701088A0 (en) | 1997-10-31 |
CN100391445C (zh) | 2008-06-04 |
BR9607752A (pt) | 1999-11-30 |
WO1997026869A1 (fr) | 1997-07-31 |
JPH11509862A (ja) | 1999-08-31 |
AU1410497A (en) | 1997-08-20 |
EP0817619A4 (fr) | 1999-02-03 |
AU722884B2 (en) | 2000-08-10 |
NZ325561A (en) | 1999-06-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU722884B2 (en) | Novel "burst-free" sustained release poly-(lactide/glycolide) microspheres | |
EP0166596B1 (fr) | Copolymères amphiphiles biodégradables | |
O'Donnell et al. | Preparation of microspheres by the solvent evaporation technique | |
AU682310B2 (en) | Salts of peptides with carboxy-terminated polyesters | |
EP0863745B1 (fr) | Polymeres biodegradables thermosensible a base de copolymeres a sequence poly(ether-ester) | |
US5916597A (en) | Composition and method using solid-phase particles for sustained in vivo release of a biologically active agent | |
CA2193203C (fr) | Microparticules de polymere destinees a l'apport des medicaments | |
US6287588B1 (en) | Agent delivering system comprised of microparticle and biodegradable gel with an improved releasing profile and methods of use thereof | |
US5665428A (en) | Preparation of peptide containing biodegradable microspheres by melt process | |
US20020076441A1 (en) | Bioactive agent delivering system comprised of microparticles within a biodegradable to improve release profiles | |
US7691412B2 (en) | Prolonged release biodegradable microspheres and method for preparing same | |
Ogawa | Injectable microcapsules prepared with biodegradable poly (α-hydroxy) acids for prolonged release of drugs | |
US7033608B1 (en) | “Burst-free” sustained release poly-(lactide/glycolide) microspheres | |
CA2216371C (fr) | Microspheres nouvelles en poly-(lactide-glycolide) a liberation controle« a l'epreuve de l'eclatement » | |
KR100511215B1 (ko) | 신규한비-일시방출형서방성폴리(락타이드/글리콜라이드)마이크로캡슐 | |
MXPA97007310A (en) | Novidae microspheres of poly- (lactida / glicolide) of release sustained without estallamie |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE |
|
17P | Request for examination filed |
Effective date: 19980130 |
|
A4 | Supplementary search report drawn up and despatched |
Effective date: 19981216 |
|
AK | Designated contracting states |
Kind code of ref document: A4 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED |
|
18R | Application refused |
Effective date: 19991209 |