Preparation andIn vitro release characteristics of hydrophilic albumin microspheres containing methotrexate and methotrexate-human serum albumin conjugates |
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Authors: | Sung-Joo Hwang Myung Gull Lee Chong-Kook Kim |
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Institution: | 1. College of Pharmacy, Chungnam National University, 305-764, Taejeon, Korea 2. College of Pharmacy, Seoul National University, 151-742, Seoul, Korea
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Abstract: | Release characteristics of five different types of hydrophilic albumin microspheres (HAM) containing different ratios of methotrexate-albumin
(MTX-HSA) conjugates to free MTX; 1∶0 (HAMC), 3∶1 (HAMC3F), 1∶1 (HAMCF), 1∶3 (HAMCF3) and 0∶1 (HAMF) were investigated in
the absence or presence of protease using dissolution tester. In all the HAMs studied except HAMC, the MTX was released bi-exponentially
in the absence of protease; an initial fast release period up to approximately 6 h, and thereafter the release rate was very
much slower. The fast release of MTX from the HAMs (such as HAMC3F, HAMCF, HAMCF3 and HAMF) at the initial phase is probably
due to the release of “physically associated” MTX on the surface and/or entrapped in the near inner surface of HAMs and the
slow release at the second phase is due to the release of entrapped free MTX from the core of the HAMs. The initial rate constants
were 7.2, 8.7, 8.5 and 5.9 times greater than the second rate constants for HAMF, HAMCF3, HAMCF and HAMC3F, respectively.
MTX release from HAMC was very slow and mono-phasic. It was at most 2.2% of the total entrapped amount by 24 h. The protease
accelerated the release of MTX from the HAMs. The percentages of MTX released from HAMs up to 24 h were 100, 89.0, 75.0, 66.0
and 61.0% for HAMF, HAMCF3, HAMCF, HAMC3F and HAMC, respectively in the presence of protease and the corresponding values
in the absence of protease were 30.2, 19.0, 10.0, 6.5 and 2.2%, respectively.In vitro release of MTX in the presence of protease varied according to the ratios of MTX-HSA conjugates to MTX; the data set from
HAMF, HAMCF3 and HAMCF fits better to monophasic first-order profile more adequately than to zero-order profile, that of HAMC3
F to mono-phasic zero-order, and that of HAMC to bi-phasic zero-order. Above results suggested that zero-order release rate
can be achieved by adjusting the ratio of MTX-HSA conjugates to MTX in the preparation of HAMs such as HAMC3F. |
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Keywords: | Hydrophilic albumin microspheres methotrexate methotrexate-human serum albumin conjugates in vitro drug release drug release by protease zero-order release |
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