| Everyone feels sad at times. People with depression feel bad all the time. Depression is a kind of affective disorder, It's caused by an imbalance of brain chemicals, along with other factors, They persist and interfere with your everyday life. Symptoms can include: Sadness,Loss of interest or pleasure in activities,Change in weight,Difficulty sleeping or oversleeping,Energy loss,Feelings of worthlessness,Thoughts of death or suicide。Fluoxetine is a potent and highly selective inhibitor of serotonin uptake in nerve center. It is the most popular choice of the treatment of severe depression disorders. It comes as a capsule, a tablet, a delayed-release (long-acting) capsule, and a solution (liquid) to take by mouth. It has very few dangerous side-effects when compared to traditional tricyclic antidepressants. But there are also some problems need to solve. Because depression needs a long-time to cure, many people stop treatment for its poor compliance for gastrointestinal irritation or just forget taking the medicine. Considering fluoxetine which also has a strong first-pass metabolism, we tried to prepare a TDDS system of the drug, and there is no report about transdermal delivery preparations of fluoxetine by now.Cataplasm is a kind of transdermal delivery system. It has not only all advantages of TDDS, but also its own superiority. It is mainly composed of hydrophilic polymers which have good biocompatibility to skin and ensure the manufacture's safety. It can make skin permeability better for the reason of stratum corneum's hydrated condition and there isn't skin irritation compared to the traditional patch.The molecular weight of fluoxetine is 345.8, and melting point is 155-157℃. Because fluoxetine is a weak base, the higher solvent's pH is, the lesser water solubility fluoxetine reached. Similarly, the higher solvent's pH is, the more drug partition into oil than water. Drug's concentrations in different solvents were determined by UV, and apparent partition coefficient was determined using shake flask method. It also can be seen that, fluoxetine get an uncommon high solubility in acetic acid solution. It is probably because that fluoxetine combined with acetic acid could form a kind of ion pair which has better solubility and lipophilicity.A simple, accurate and sensitive high-performance liquid chromatography (HPLC) assay was established to measure the content of FLU in vitro. The condition was as follows: Diamonsil ODS C18 column(4.6mm×250mm,5μm), UV detective wavelength 226nm, Methanol-25 mM potassium dihydrogen phosphate buffer (pH3.0) (70:30) was used as mobile phase at flow rate of 1.0ml·min-1. as the result, the tR of fluoxetine is about 5.9min and R﹥1.5. This method was used to analysis concentrations of fluoxetine in dissolution and skin penetration experiments.To study the effects of enhancers on the transdermal delivery of fluoxetine hydrochloride, different penetration rates of fluoxetine hydrochloride through SD-rat abdominal skin in vitro were measured using Valia-Chien diffusion cells. All of the penetration enhancers works except propanediol compared with blank group. Azone with PG or NMP improved the transdermal delivery of fluoxetine hydrochloride most. So penetration of fluoxetine hydrochloride on rat skin benefited most from the reasonable combined use of enhancers. finally, we chose Azone,PG,NMP as the enhancers in the formulation considered in the following experiments.The optimal formulation of FLU cataplasm was obtained by using uniform design to study the influences of different ingredients. We chose NP-700,dihydroxyaluminum aminoacetate,citric acid,glycerol as the factors, adhesive strength and cohesive strength as the indexes. The results were analysised by multiple linear regressions.Then we put enhancers into the optimized formulation, and we finally decided to chose Azone,NMP,PG as a whole ingredients to make fluoxetine penetrate most. The permeation tests through rat skin in vitro demonstrated that the fluoxetine cataplasm exhibited zero-order kinetics.The drug release from the fluoxetine cataplasm fitted to the Higuchi equation .The accelerated test showed that the preparation was statble, the drug contents and the weight differences were accorded with Pharmacopoeia of the People's Republic of China of 2005 edition. The study on the rat skin irritation and allergies of preparations were carried out, and it was shown that fluoxetine cataplasm is safe and effective.Finally the pharmacokinetics research was conducted in rats. The FLU cataplasms were fixed in the rats'back. Concentrations of fluoxetine in plasma samples were determined by HPLC. We concluded the curve of the fluoxetine concentrations in rat plasma at the time, and calculated it's pharmacokinetics parameters. The drug concentration-versus-time patterns for transdermal administration indicated a delayed absorption rate and an apparent prolongation of the absorption phase, when compared with patterns for oral administration. The results also showed that the maximum serum concentration decreased, the MRT extended. |
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