Validation of a cage implant system for assessing in vivo performance of long-acting release microspheres.
Here we describe development of a silicone rubber/stainless steel mesh cage implant system, much like that used to assess biocompatibility of biomaterials [1], for easy removal of injectable polymer microspheres in vivo. The sterile cage has a type 316 stainless steel mesh size (38 μm) large enough for cell penetration and free fluid flow in vivo but small enough for microsphere retention, and a silicone rubber shell for injection of the microspheres. Two model drugs, the poorly soluble steroid, triamcinolone acetonide, and the highly water-soluble luteinizing hormone-releasing hormone (LHRH) peptide superagonist, leuprolide, were encapsulated in PLGA microspheres large enough (63-90 μm) to be restrained by the cage implant in vivo. The in vitro release from both formulations was followed by ultra-performance liquid chromatography (UPLC) with and without the cage in a standard release media, PBS pH 7.4 + 0.02% Tween 80 + 0.05% sodium azide, at 37 °C. Pharmacokinetics (PK) in rats was assessed after SC injection or SC in-cage implantation of microspheres with plasma analysis by LC-MS/MS or EIA. Tr-A and leuprolide in vitro release was largely unaffected after the initial burst irrespective of the cage or test tube incubation vessel and release was much slower than observed in vivo for both drugs. Moreover, Tr-A and leuprolide pharmacokinetics with and without the cage were highly similar during the 2-3 week release duration before a significant inflammatory response was caused by the cage implant. Hence, the PK-validated cage implant provides a simple means to recover and evaluate the microsphere drug carriers in vivo during a time window of at least a few weeks in order to characterize the polymer microsphere release and erosion behavior in vivo. This approach may facilitate development of mechanism-based in vitro/in vivo correlations and enable development of more accurate and useful in vitro release tests.
Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, North Campus Research Complex, 2800 Plymouth Road, Ann Arbor, MI, 48109, United States.
Amy C
AC
Doty
Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, North Campus Research Complex, 2800 Plymouth Road, Ann Arbor, MI, 48109, United States.
Keiji
K
Hirota
Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, North Campus Research Complex, 2800 Plymouth Road, Ann Arbor, MI, 48109, United States.
Karl F
KF
Olsen
Department of Internal Medicine, Biomedical Science Research Building, 109 Zina Pitcher Place, University of Michigan, Ann Arbor, MI, 48109-2200, United States.
Naoya
N
Sakamoto
Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, North Campus Research Complex, 2800 Plymouth Road, Ann Arbor, MI, 48109, United States.
Rose
R
Ackermann
Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, North Campus Research Complex, 2800 Plymouth Road, Ann Arbor, MI, 48109, United States.
Meihua R
MR
Feng
Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, United States.
Yan
Y
Wang
Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, United States.
Stephanie
S
Choi
Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, United States.
Wen
W
Qu
Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, North Campus Research Complex, 2800 Plymouth Road, Ann Arbor, MI, 48109, United States.
Anna
A
Schwendeman
Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, North Campus Research Complex, 2800 Plymouth Road, Ann Arbor, MI, 48109, United States; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, United States. Electronic address: schwende@umich.edu.
Steven P
SP
Schwendeman
D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D065546:Drug Liberation; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists / Q000737:chemistry; D006801:Humans; D007279:Injections, Subcutaneous; D007700:Kinetics; D019344:Lactic Acid / Q000737:chemistry*; D016729:Leuprolide / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D008863:Microspheres; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D012825:Silicon; D012995:Solubility; D013193:Stainless Steel / Q000737:chemistry*; D014222:Triamcinolone Acetonide / Q000737:chemistry / Q000493:pharmacokinetics; D014867:Water / Q000737:chemistry
D001672:Biocompatible Materials; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D014867:Water; D013193:Stainless Steel; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D007987:Gonadotropin-Releasing Hormone; D019344:Lactic Acid; D016729:Leuprolide; D014222:Triamcinolone Acetonide; D012825:Silicon
Cage model; Controlled release; IVIVC; PLGA; Release kinetics