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Study on Sustained-release Microspheres and Dry Powder Inhalers of IFNα-2b

Author: LiZhiPing
Tutor: MeiXingGuo
School: PLA Military Academy of Medical Sciences
Course: Pharmacy
Keywords: IFNα-2b microspheres DPIs PEG/PBT PLGA
CLC: R94
Type: PhD thesis
Year: 2007
Downloads: 420
Quote: 1
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Abstract


Interferons(IFNs) are proteins with multi-function, including antiviral, antiproliferative and some immunomodulatory effects. As a member of IFNs, IFNαexhibited promising anti-cancer activities and effective anti-virus activities. Now IFNαis the first choice for counteracting hepatitis C virus (HCV) and chronic myelocytic leukemia (CML), and it is the most general cytokine for renal carcinoma, too.With a short half life and common injections in clinic, IFNαis often administrated 3-5 times per week. This administration route is very inconvenient and easily results in infection because of injection, so its application in clinic is limited severely. There are two resolvents for the problem, one is to develop sustained-release preparations such as microspheres to extend effectual time and reduce administration frequency, and the other is to develop preparations replacing for injections such as DPIs.There are many works thrown into development of IFNs preparations recently, and PEGlyted IFNαhas been shown in market, but it sustains action just for about 1 week and is administered still by injection. Microspheres as drug delivery systems have the potential for providing controlled release of drugs and IFNαmicrospheres have also been reported in the gross, but these extended-release preparations can’t release IFNs completely and long enough. Pulmonary preparations containing IFNs are always composed of HSA to stable drugs, and this provides potent dangers of infection. So IFNα-2b microspheres and DPIs were preparaed to meet IFNs’ clinical requirements in the study.Firstly, ELISA method for content of IFNα-2b, CPE method for valence of IFNα-2b and Bradford method for total amount of proteins were established. Gelatin powders were preparaed by freeze-drying and triturating the mixture of IFNα-2b, gelatin solution and metal solutions. Then the formulation of gelatin powders was confirmed through investigating effects of several factors on characters of gelatin powders, and the average diameter of optimal gelatin powders was about 5μm, and encapsulation efficiency of IFNα-2b was above 85%.PEG/PBT sustained-release microspheres were preparaed with IFNα-2b entrapped in gelatin powders. Effects of factors on characters of microspheres were invesgitated and the formula was optimized by orthogonal design experiments with additional amount of PLGA, ZnCO3 and gelatin powders as investigated factors. 3 batches of IFNα-2b PEG/PBT-PLGA microspheres were preparaed according to optimal formula and characters of microspheres were investigated. It is shown that microspheres have burst release of about 16% and could sustain releasing IFNα-2b longer than 20 days with cumulative release above 80%, and it is also shown that the technology of manufacturing microspheres is repeatable.Stability of IFNα-2b PEG/PBT-PLGA microspheres were tested under different conditions. It was indicated that these microspheres were unstable at high temperature, highlight andγray, but these microspheres were stable at accelerated tests and long term tests in one month.The release mechanism was also investigated by fitting in vitro release of IFNα-2b PEG/PBT-PLGA microspheres with different release models and checking morphology, weight loss and particle sizes of PEG/PBT microspheres, PLGA microspheres and PEG/PBT-PLGA microspheres during release in vitro. It was shown that the in vitro release of IFNα-2b PEG/PBT-PLGA microspheres fits zero-order release, and IFNα-2b in PEG/PBT-PLGA microspheres was released by diffusion.The release of IFNα-2b PEG/PBT-PLGA microspheres in rats were also investigated with IFNα-2b injections as reference, and results showed that there was a burst release at 4h and then IFNα-2b concentration in serum was steady until 14days. Correlation between in-vitro and in vivo release was analyzed, and it is shown that there was a good relationship between in-vitro and in vivo release and release amount of IFNα-2b in vivo at n day was equavalent to the amount in vitro at (2n-1) day. The formula of DPIs was also optimized by sieving several additives with encapsulation efficiency of IFNα-2b, particle size and hydroscopicity as reference. 3 batches of DPIs were preparaed and their characters were investigated. It was shown that the average diameters of powders were smaller than 7μm, hydroscopicity at RH75% for 24h were lower than 8%, encapsulation efficiency of IFNα-2b were higher than 85%, and the amount of first and second distribution in particle distribution tests were higher than 55%, and it was also shown that this technology was repeatable.Stability of IFNα-2b DPIs was tested under different conditions. It was indicated that these powder were unstable at high temperature and high humidity, highlight andγray, but these powders were stable at accelerated tests and long term tests in 5 months.Characters of IFNα-2b DPIs in rats were also investigated with IFNα-2b subcutaneous injections as reference, and it was shown Cmax was obtained at 0.39h. The bioequvalence between IFNα-2b DPIs and subcutaneous injections was analysed by 3p97 with AUC0-inf Cmax and Tmax as responses, and it was proved that these two kinds of preparations were non bioequvalence. The investigation on irritation and safety of IFNα-2b DPIs showed that IFNα-2b DPIs could perhaps reduce slight inflammation.Overall, characters of IFNα-2b PEG/PBT-PLGA microspheres preparaed in this study was satisfying both in vitro and in vivo, which showed a good way to stabilize IFNα-2b in microspheres. IFNα-2b DPIs were also satisfying, and it has the potential for further development. Two parts of this study have been applied for patent of the People’s Republic of China.

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