| Koumine, a monoterpenoid indole alkaloid, is a major alkaloidal constituent of Gelsemium elegans Benth.. Our previous works showed that koumine had significant pharmacological effects for chronic pain and rheumatoid arthritis with low toxicity, which indicates that koumine has a great pharmaceutical potential. As a result, various preparation was prepared for further research. Koumine odinary oral preparation, had several problems such as wide fluctuation of blood drug concentration and poor patients’compliance of patients. Otherwise, koumine sustained-release preparation could increase patients’ compliance by reducing the times of taking drugs and reduce the plasma concentration fluctuations. In this paper, we obtained koumine film-coating sustained-release pellets which possessed12h release in vitro by adjusting the formulation of pellets as well as the technological optimization of fluid bed coating. Subsequently, we investigated the preliminary stability of koumine film-coating sustained-release pellets via influence factors test and acceleratation test. At last, we determinated blood drug concentration-time curve of koumine sustained-release capsules in beagle dogs after single oral administration, evaluated its relative bioavailability and bioequivalence with a self-made koumine conventional tablet as the reference preparation. All the results provided the scientific baisis of large-scale preparation of koumine film-coating sustained-release pellets and laid the foundation for the development of koumine with independent intellectual property rights.This research contains three sections as follows:1. Preparation of koumine film-coating sustained-release pelletsThe formulation and prepared technology of koumine film-coating sustained-release pellets were investigated in the light of yield of pellets, pellets roundness and release rate of koumine. The results showed that30%coating weight of Surelease in koumine susuaind-release pellets kept its release well in12h. As a binder layer,15g/L5cps hydroxypropyl methyl cellulose (HPMC) improved the yield of sustained-release pellets and obtained good roundness, and as an isolation layer,1%5cps HPMC increased the releasing stability of koumine film-coating sustained-release pellets in12h. To sum up, the optimized formulation was as follows:Prescription Mass（mg）Blank sucrose pellets10000Koumine100HPMC300Surelease300The content of koumine in the above pellets is0.67%. Meanwhile, the reproducibility of preparation of the pellets and its release uniformity are fine in this study.2. Preliminary stability study of koumine sustained-release capasuleWe investigated the preliminary stability of koumine sustained-release pellets capasule with the No.3caspsule filled with300mg pellets, specifications for the2mg/particle. The results of influence factors test showed that at60℃for10days, or at relative humidity of90%at room temperature for10days, or illumination in the light of4000LX for10days, its release rate changed in vitro obviously, sugusting that the preparation stability is infuencede deeply by dramatic factors of high temperature, high humidity and light. we conducted the cceleratation test based on the results of influence factors test, the results showed that at the temperature of40℃and relative humidity of75%for6months, its release rate in vitro, appearance and color didn’t changed significantly. The results provide experimental basis of storage conditons of koumine sustained-release pellets capasule.3. Evaluation of the release characteristics of koumine sustained-release capsule in beagle dogsLC-MS/MS method of determination for koumine blood drug concentration was established to study the capsules’ release characteristics in beagel dogs. In this part, we determinated blood drug concentration-time curve of koumine sustained-release capsules in beagle dogs after single oral administration, and evaluated its release characteristics with a self-made koumine conventional tablet as the reference preparation. The results showed that the capsule did not possess the characteristic of sustained releaseing, though it is bioequivalent to the conventional tablet. It suggested that the preparation of this koumine sustained-release pellets and its evaluation method in vivo should be further optimized. In a word, This study provided a reference for the large-scale preparation of koumine film-coating sustained-release pellets. |
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