| At least two-thirds of patients with advanced cancer report pain(WHO,1996).Pain is typically experienced most of the time and is best managed with a fixed scheduled opioid regimen. Fentanyl citrate, a potent synthetic opioid widely used in anesthesiology, has been proposed for the treatment of cancer pain, especially for breakthrough pain.When administered orally, fentanyl is subject to extensive first pass metabolism by the liver resulting in a low bioavailability.Therefore, products are preferably formulated in injection clinically, but unconvenience. The buccal route, as an alternative to other traditional methods of systemic drug administration, is a subject of growing interest because of its numerous advantages. It is well-known that the absorption of therapeutic compounds from the oral mucosa provides a direct entry of the drug into the systemic circulation, therefore, avoiding the first-pass hepatic metabolism and gastrointestinal drug degradation, which is associated with oral adminstration. Oral transmucosal fentanyl citrate (OTFC) has been shown to be an effective drug delivery method for breakthrough pain relief in several studies. Fentanyl is absorbed from the OTFC unit directly into the circulation through the oral mucosa,allowing the patient to obtain effective opioid levels more rapidly than oral administration. However, due to the involuntary swallowing and continuous dilution by the salivary flow, the conventional buccal dosage forms are restricted to short periods of time and, consequently, controlled drug release is not within the scope of such formulations. From the above-mentioned points of view, our present study was to develop new buccal devices which can adhere to the oral mucosa, withstanding salivation, tongue movements and swallowing for a significant period of time. Since this drug delivery is easily accessible and can be even removed from the siteof application, stopping the input of drug whenever desired, it is well accepted by patients, and patients can achieve self-medication.In the first part of our present study, the permeability of fentanyl via buccal mucosa has been investigated in order to study its permeation mechanism and its feasibility of drug delivery through buccal mucosa. The extricated hamster oral mucosa and anesthetized rats' oral mucosa were designed to investigate the effect of pH on permeation of fentanyl through buccal mucosa in its solutions and preparations respectively. The results indicate that the absorption of fentanyl through oral mucosa is affected by pH apparently, and obeys the pH-partition hypothesis. The permeation rate depends on the vehicles' pH both in vitro and in situ under our test condition. The results also suggest that fentanyl is transported through transcellular pathway by passive diffusion. Since the drug in the dosage is over-saturated, fentanyl as a weak basic compound is used to prepare a buccal drug delivery, which can be increased the unionized fraction or solubility by pH. And it is feasible to develop a drug delivery with fast- action and a comparatively constant penetration rate.In the second part of our study,a new buccal drug delivery of fentanyl citrate was proposed. From a technological point of view, an ideal buccal dosage form must have three properties:(i) It must maintain its position in the mouth for a few hours,(ii)release the drug in a controlled fashion and (iii) provide drug release in a unidirectional way towards the mucosa. Therefore, the first step in the development of a buccal device is the selection of an appropriate adhesive. A number of bioadhesive polymers have been investigated, such as sodium carboxymethylcellulose, chitosan, hydroxypropylcellulose, hydroxypropyl methylcellulose and alginate sodium as well. By the primary evaluation, we proposed two new mucoadhesive bilayered devices, one made of alginate sodium, CMC-Na and PVA as bioadhesive materials and ethylcellulose(EC) as an impermeable backing material, the other made of chitosan and HPC as bioadhesive materials and ethylcellulose(EC) as an impermeable backing material the same. The optimum ratio of the materials in the formulation was selected by employing orthogonal design and the two buccal devices were characterized by measuring the bioadhesion , retention time in mouth , appearance , film dissolving time, drug release and permeability as the criterions.The results indicate that sodium alginate,CMC-Na and PVA in a ratio of 2 : 1 '. 2 and chitosan-HPC in a ratio of 4 '. 1 was optimum ratios for above two formulations respectively.According to the above results, the two buccal devices were developed by spreading drug on bioadhesive layer and EC as an impermeable backing material, which is called protective layer. The two devices were characterized by measuring in vitro drug release behavior, bioadhesive properties and permeability through excised oral mucosa of golden hamsters.The test results of the device made of PVA, CMC-Na and alginate sodium show that its bioadhesive force was (202 ±4.8) g *cm'2, the duration in vivo was 120 min. Its release curve conforms to Higuchi formulation in the first 60min.and also conforms to first-order model, their correlation coefficients (R) was 0.9957 and 0.9951 respectively. This suggests that the drug delivery is a sustained-release system, and a penetration rate of 7.294 n g *cm"2 'h'1 was observed in vitro. Addition of glycyrrhizin(GL) as a corrigent to the films significantly increased the fentanyl release rate and penetration(P<0.05) with a higher penetration rate of 10.527 H g ? cm"2 ? h"1, though a little decrease of bioadhesive force was observed.The test results of the other device with chitosan-HPC in a ratio of 4 : 1, show that its bioadhesive force was (125 + 6.0) g ? cm'2, the oral retention time in volunteers of the formulation was 54 min. Fentanyl completely released from this dossage within an hour, and after addition of GL, drug completely released from the dossage within half an hour, and a penetration rate of 9.874 n g ? cm"2 ? h"1 was observed in vitro. Addition of glycyrrhizin as a corrigent to the dossage significantly increased the fentanyl release rate and penetration (P<0.05) with a higher penetration rate of 16.707 u g ?cm"2 'h'1, though a little decrease of bioadhesive force was observed (P>0.05).Finally, the preliminary stability test on the two buccal adhesive films were performed under 40oC±2"C and relative humidity of 75% ±5%. The content of fentanyl was determined by HPLC. After 0,1, 2, 3 months, the mean drug contents of the buccal adhesive films with alginate sodium as a base from five batches was 98.45%, 98.14%, 97.89% and 97.68%, the mean duration time in vivo was 100.0 min.,98.2min.,99.5 min. and 98.5 min. respectively. After 0,1, 2, 3 months.the mean drug contents of the buccal adhesive films with chitosan as a base from five batches was 99.44%, 99.04%, 98.52% and 98.26%, the mean duration time in vivo was 52 min.,51.7 min., 49.0 min.and 47.7 min. respectively. The t-test performed on above parameters revealed that after three months the difference of drug content and the duration in vivo of these two drug delivery was not significant (P>0.05). An initial conclusion can be made that fentanyl buccal adhesive films are stable within three months.
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