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香港中文大学研究人员 ( 现职)
| 黎嘉麟先生 (药剂学院) |
| 韩灏小姐 (药剂学院) |
| 方圆博士 (药剂学院) |
| 李伟业教授 (药剂学院) |
| 李浩然博士 (药剂学院) |
| 林泰宁教授 (药剂学院) |
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摘要
Background: Parkinson’s disease (PD) is a major threat to aging population, which is well recognized as a global trend. It is generally believed that PD is caused by a loss of dopaminergic neurons. Dopamine receptor agonists have been applied alone or in combinations with dopamine precursors (L-DOPA) in the treatment of PD, with the ultimate goal of reducing the dyskinesia and on–off effects caused by L-DOPA. Ropinirole, a non-ergoline type dopamine receptor agonist, has been widely used due to its favorable safety profiles and the ability for protecting the brain tissue against oxidative injury. However, this drug undergoes extensive first-pass metabolism, which accounts for its short half-life and low oral bioavailability. As a result, frequent administration of ropinirole is necessary and this may negatively impact patient compliance. Also, due to the tremor, rigidity, and limited mobility experienced by PD patients, particularly during the “off-period”, there is a pressing need to devise formulations that allow simple and easy administration and fast drug action. In this study, we aimed at fabricating and characterizing orally-dissolving films of ropinirole and assessing their in vivo pharmacokinetic performance after sublingual or buccal administration.
Methods: Ropinirole oral films were prepared by a standard solvent-casting method and the drug content, disintegration, dissolution, etc. were characterized. A physical stability study of the ropinirole oral films was conducted under three standard ICH conditions. In vitro toxicity was determined by a LDH release assay. Finally, the pharmacokinetic studies were conducted by three different routes (i.e. oral, sublingual and buccal) of administration in rabbits.
Results: The ropinirole oral films appeared to be off-white with opacity and consisted of HPMC, PEG and ropinirole. The average drug content of the oral films is 99.7 %,
which is very close to the theoretical value. Regarding content uniformity, the standard deviation is about 2.4 %. The oral film was fast-dissolving and complete drug release was achieved within 2 minute. In addition, the ropinirole oral film started to disintegrate within 10 seconds and complete disappearance of the film was achieved within 2 minutes. The ropinirole oral films were shown to be physically stable for at least 28 days under three standard ICH conditions. Compared with the LDH levels at time = 0, both ropinirole and the drug-loaded oral film did not trigger significant LDH release after 4-hour incubation with sublingual tissues, which indicates our formulation is relatively safe and does not cause any tissue damage. After buccal or sublingual administration of the oral film, ropinirole could be detected in the plasma within 15 minutes at 40 to 50 ng/mL, indicating that there was fast drug absorption into the systemic circulation. Relative to the oral route of administration, the sublingually and
buccally applied oral films increased the AUC0 → 6hour by about 7x, which was determined to be statistically significant (unpaired student t-test, p<0.05), and this may
be attributable to avoidance of first-pass metabolism.
Conclusions: We have developed a ropinirole oral film that improved bioavailability in vivo after sublingual or buccal administration. This formulation can potentially overcome the biopharmaceutic challenges of ropinirole and provide a convenient means of anti-PD drugs administration.
着者ZHANG B, Fang Y, Han H, Lai K L, Li Q, Zhang S, Li H Y, Lam T N, Lee W Y
会议名称American Association of Pharmaceutical Scientists Annual Meeting and Exposition
会议开始日13.11.2016
会议完结日17.11.2016
会议地点Denver, USA
会议国家美国
出版年份2016
语言美式英语
