| Galanthamine hydrobromide is a competitive and reversible acetylcholinesterase inhibitor which is used in the treatment of poliomyelitis, myasthenia gravis, postoperative atonic ileus, glaucoma and Alzheimer’s disease (AD), and which is used as antagonists of nondepolarizing muscle relaxants and curare’s action. Galanthamine hydrobromide is an effective and well tolerated drug which is used today in the treatment of mild to moderate AD for it crosses the blood-brain barrier easily and its inhibition is long and selective. But the majority of adverse events are mild to moderate in gastrointestinal symptoms such as nausea, vomiting, diarrhea and so on when administered orally.Transdermal patch is a transdermal delivery drug system (TDDs) and also a transdermal therapeutic system (TTS), the administered advantages of which are able to keep pharmacodynamic actions for a long time and avoid adverse events in gastrointestinal symptoms. Accordingly, it was the object of the study to provide galanthamine hydrobromide in the form of a transdermal patch and its preparative method. Transdermal patch of galanthamine hydrobromide was developed, on which the matrix, preparation, quality, released performance and permeation performance across skin in vitro were studied.The release of galanthamine hydrobromide in 11 kinds of matrix consisted of different proportion of PVA-1788 and CMC-Na was investigated with dissolution tester while the accumulative release amount was served as index. It was shown that the accumulative release amount in 60 min of 11 kinds of matrix is larger than 90% revealing perfect release performance. The largest accumulative release amount of all is the matrix which PVA-1788 proportion is 100% and 90% while the smallest is 50%.5 kinds of pressure sensitive adhesives (PSA) were investigated with Franz dissolution cell while the accumulative release amount was served as index. The results showed the largest accumulative release amount of all is the pressure sensitive adhesive“2102”.A high performance liquid chromatography (HPLC) method for determination the content of galanthamine hydrobromide in transdermal receiver solution was developed. An Alltima Phenyl column (250mm×4.6mm, 5μm) was used with the mobile phase consisted of acetonitrile-phosphate buffer (20 mmol/L KH2PO4 solution 1000 ml added 1.4 ml triethylamine and adjusted pH to 3.3 by phosphoric acid) (8:92) at a flow rate of 0.65 ml/min and the column temperature was at 30℃.The detection wavelength was at 210 nm and the injection volume was 20μl. It is shown that in the condition, the endogenous substance and the adjuvant material in transdermal receiver solution were not interfered the determination, and the calibration curve was linear in the range of 4.524-904.8 ng, (R2=1.000, n=10) for galanthamine hydrobromide.The effect of 12 kinds of permeation enhancers (e.g. oleic acid, azone, camphor, borneol and menthol) on permeation performance across porcine skin in vitro was studied by the methods of Franz dissolution cell and HPLC while the accumulative permeation amount, the permeation flux and the lag time were served as indexes. The results showed that the effects of permeation enhancers on the accumulative permeation amount had significant difference (F=2.752, P=0.013) and the largest accumulative permeation amount of all was borneol contrast to the control group (P=0.006), and then azone (but having no significant difference, P=0.113). The effects of permeation enhancers on the permeation flux had significant difference (F=2.911, P=0.010) and the largest permeation flux of all was borneol contrast to the control group, of which the enhance ratio was 4.79 (P=0.002), and then azone, of which the enhance ratio was 3.06 (but having no significant difference, P=0.220). But the effects of permeation enhancers on the lag time had no significant difference (F=1.784, P=0.101).The prepared transdermal patch of galanthamine hydrobromide consisted of backing layer (missing now), drug reservoir, pressure sensitive adhesive layer and protective layer, wherein the drug reservoir comprised galanthamine hydrobromide, water-soluble high polymer matrix and plasticizers, and wherein the pressure sensitive adhesive layer comprised galanthamine hydrobromide, hydrophilic pressure sensitive adhesive and permeation enhancers. In the drug reservoir, the drug dosage was 0.4 g/400cm2, and the dosage of the water-soluble high polymer matrix (PVA- 1788: CMC - Na = 7: 3) was 10 g/400cm2, and the dosage of the plasticizer glycerine was 0.3 g/400cm2. In the pressure sensitive adhesive layer, the drug dosage was 0.32 g/400cm2, and the dosage of the hydrophilic pressure sensitive adhesive (code name: 2102) was 4.5 g/400cm2, and the permeation enhancers were the mixture of borneol and azone, the dosages of which were both 0.3 g/400cm2, The dosage of the prepared transdermal patch of galanthamine hydrobromide was 1.8 mg/cm2, and the administration areas were 10 cm×10 cm.The quality evaluation of the transdermal patch of galanthamine hydrobromide included moisture content, adhesive force, drug content, release performance and permeation performance across skin in vitro. It was regulated that moisture content be no less than 10%, tacking strength be not respectively lower than steel ball No.12 and cohesion strength be in displacements of 3.0～6.0 cm when 200 g tensile force on the length direction of 10cm×2.5cm patch in 30 min. The determination of the transdermal patch of galanthamine hydrobromide was developed by the first derivative UV-spectrophotometry. This method is simple, rapid, and accurate and the results showed that the contents of the patches in 6 batches were 1.67±0.05 mg/cm2. The release of the transdermal patch of galanthamine hydrobromide was determined by the methods of Franz dissolution cell and the first derivative UV-spectrophotometry. It showed that the accumulative release amounts in 60 min of 4 batches of patches were all larger than 95%, and the release curve fitted Higuchi equation, the release rate of which was 461.9±41.9μg/cm2-h1/2. The permeation performance across porcine skin in vitro was studied by the methods of Franz dissolution cell and HPLC. It showed that the accumulative permeation amounts in 24 h of 6 batches of patches were 20.904±3.050μg/cm2, and the permeation curve fitted zero-order kinetic equation, the permeation flux and the lag time of which were 1.270±0.229μg/cm2.h and 4±0.7h. |
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