PART 1 Development of self-microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs The main purpose of this work is to prepare self-microemulsifying drug delivery system (SMEDDS) for oral bioavailability enhancement of a poorly water soluble...
PART 1 Development of self-microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs The main purpose of this work is to prepare self-microemulsifying drug delivery system (SMEDDS) for oral bioavailability enhancement of a poorly water soluble drug, simvastatin. Solubility of simvastatin was determined in various vehicles. SMEDDS is mixtures of oils, surfactants, and cosurfactants, which are emulsified in aqueous media under conditions of gentle agitation and digestive motility that would be encountered in the gastro-intestinal (GI) tract. Pseudo-ternary phase diagrams were constructed identifying the efficient self-emulsification region and particle size distributions of the resultant microemulsions were determined using a laser diffraction sizer. Optimized formulations for in vitro dissolution and bioavailability assessment were Carpryol 90 (37%), Cremophor EL (28%), and Carbitol (28%). The release rateof simvastatin from SMEDDS was significantly higher than the conventional tablet. The prepared SMEDDS was compared with the conventional tablet (Zocor) by administering with prefilled hard capsules to fasted beagle dogs. The absorptionof simvastatin acid from SMEDDS form resulted in about 1.5-fold increase in bioavailability compared with the conventional tablet. Our studies illustrated the potential use of SMEDDS for the delivery of hydrophobic compounds such as simvastatin by the oral route. PART 2 Preparation of Solid Dosage Form containing SMEDDS of Simvastatin by Microencapsulation The objective of this study was to solidify the simvastatin self-microemulsifying drug delivery system (SMEDDS) and to improve the encapsulation efficiency of solidified alginate beads using sodium alginate. Typical simvastatin SMEDDS was composed of various oils, surfactants and cosurfactants. Also solidified-alginate beads was prepared by crosslinking liquid emulsion mixtures containing sodium alginate and other excipients (cetylpyridinum chloride (CP-Cl), hydroxypropyl methylcellulose, starch and so on). in CaCl_(2) solution, it has been investigated that the drug release pattern and encapsulation efficiency were varied with the ratio of cationic lipid (CP-Cl). Solidified sodium alginate beads containing simvastatin SMEDDS were redispersed into media without re-aggregation. Oil droplet size of redispersed solidified-beads in media produced smaller than the initial size. The density of beads and drug loading amount were increased with increasing cationic lipid content. These systems have advantages of storage stability and predictability of drug release rate. PART 3 Release and characterization of multiple coated pellets containing melatonin Melatonin (MT) is an indole amide pineal hormone. It has not only very short half-life but also pH-sensitive property. The sustained release dosage form which delivers MT in a circadian fashion over 8h is clinical value. The purpose of this study is to prepare sugar beads using multiple coating methods and enteric-coated in a sustained release to evaluate in vitro release characteristics in simulated gastric and intestinal fluids. The Eudragit^(�) as a polymer, sustained release membrane, and triethylcitrate (TEC) as a plasticizer were used. Multi-coated melatonin delivery system was composed of sugar, various excipients, eudragit^(�) and enteric materials (e.g. hydroxy propyl methyl cellulose phthalate, HPMCP), and prepared by fluid bed coater. The dissolution test was carried out using the basket method at a stirring speed of 100 rpm at 37 ℃ in simulated gastric (pH 1.2) and intestinal fluid (pH 7.4). The released amount of MT was determined by High performance liquid chromatography method. The morphologies of surface and cross section of multi-coated beads were observed by scanning electron microscope. Size of multi-coated sugar beads was ranged over 1000 ~ 1300 ㎛. The release rate of MT from coated beads was limited in simulated gastric fluid (pH 1.2), but it was sustained in intestinal fluid (pH 7.4) during 3 ~ 8 hours. The MT beads may provide small-intestine-targeted device for oral delivery. Studies on animal and relative experiment are in process. PART 4 Preparation of self-emulsifying drug delivery system for piroxicam ; in vitro transdermal release and permeation studies Piroxicam is a potent synthetic opiate commonly used for surgical analgesia and sedation. It is approximately 200 times more potent than morphine, has a rapid onset (1-2 min), and short duration of action (30-60 min). Due to its potency and quick onset, even a very small dose of fentanyl can lead to sudden death. Morever, the expected concentration range of fentanyl is very low. A concentration of 1-10 ng/mL in plasma is effective therapeutic range for analgesia. Therefore, the detection of lower levels of the compound from analgesia dose is important. In addition, intravenous administraion of fentanyl results in a relatively short half-life, about 3.7 hr in plasma, and simple parenteral administration of fentanyl may not be fully effective, so frequent injections and continuous infusion are required to ensure adequate plasma levels. However, these methods have the disadvantage of potentially causing irreversible damage to nerve or surronding tissue due to fluctuations in concentration and high levels of anesthetic. Additionally, anesthetic delivered in the form of pulse instead of zero-order kinetics may aggravate adverse reactions due to over-dosage. Therefore, a sustained release system might be needed to prolong the action of local anesthetic as well as to avoid the inconvenience of patients and to maintain constant therapeutic levels. The development of long-acting local anesthetics is also needed for postoperative analgesia and control of chronic pain of cancer patients.
PART 1 Development of self-microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs The main purpose of this work is to prepare self-microemulsifying drug delivery system (SMEDDS) for oral bioavailability enhancement of a poorly water soluble drug, simvastatin. Solubility of simvastatin was determined in various vehicles. SMEDDS is mixtures of oils, surfactants, and cosurfactants, which are emulsified in aqueous media under conditions of gentle agitation and digestive motility that would be encountered in the gastro-intestinal (GI) tract. Pseudo-ternary phase diagrams were constructed identifying the efficient self-emulsification region and particle size distributions of the resultant microemulsions were determined using a laser diffraction sizer. Optimized formulations for in vitro dissolution and bioavailability assessment were Carpryol 90 (37%), Cremophor EL (28%), and Carbitol (28%). The release rateof simvastatin from SMEDDS was significantly higher than the conventional tablet. The prepared SMEDDS was compared with the conventional tablet (Zocor) by administering with prefilled hard capsules to fasted beagle dogs. The absorptionof simvastatin acid from SMEDDS form resulted in about 1.5-fold increase in bioavailability compared with the conventional tablet. Our studies illustrated the potential use of SMEDDS for the delivery of hydrophobic compounds such as simvastatin by the oral route. PART 2 Preparation of Solid Dosage Form containing SMEDDS of Simvastatin by Microencapsulation The objective of this study was to solidify the simvastatin self-microemulsifying drug delivery system (SMEDDS) and to improve the encapsulation efficiency of solidified alginate beads using sodium alginate. Typical simvastatin SMEDDS was composed of various oils, surfactants and cosurfactants. Also solidified-alginate beads was prepared by crosslinking liquid emulsion mixtures containing sodium alginate and other excipients (cetylpyridinum chloride (CP-Cl), hydroxypropyl methylcellulose, starch and so on). in CaCl_(2) solution, it has been investigated that the drug release pattern and encapsulation efficiency were varied with the ratio of cationic lipid (CP-Cl). Solidified sodium alginate beads containing simvastatin SMEDDS were redispersed into media without re-aggregation. Oil droplet size of redispersed solidified-beads in media produced smaller than the initial size. The density of beads and drug loading amount were increased with increasing cationic lipid content. These systems have advantages of storage stability and predictability of drug release rate. PART 3 Release and characterization of multiple coated pellets containing melatonin Melatonin (MT) is an indole amide pineal hormone. It has not only very short half-life but also pH-sensitive property. The sustained release dosage form which delivers MT in a circadian fashion over 8h is clinical value. The purpose of this study is to prepare sugar beads using multiple coating methods and enteric-coated in a sustained release to evaluate in vitro release characteristics in simulated gastric and intestinal fluids. The Eudragit^(�) as a polymer, sustained release membrane, and triethylcitrate (TEC) as a plasticizer were used. Multi-coated melatonin delivery system was composed of sugar, various excipients, eudragit^(�) and enteric materials (e.g. hydroxy propyl methyl cellulose phthalate, HPMCP), and prepared by fluid bed coater. The dissolution test was carried out using the basket method at a stirring speed of 100 rpm at 37 ℃ in simulated gastric (pH 1.2) and intestinal fluid (pH 7.4). The released amount of MT was determined by High performance liquid chromatography method. The morphologies of surface and cross section of multi-coated beads were observed by scanning electron microscope. Size of multi-coated sugar beads was ranged over 1000 ~ 1300 ㎛. The release rate of MT from coated beads was limited in simulated gastric fluid (pH 1.2), but it was sustained in intestinal fluid (pH 7.4) during 3 ~ 8 hours. The MT beads may provide small-intestine-targeted device for oral delivery. Studies on animal and relative experiment are in process. PART 4 Preparation of self-emulsifying drug delivery system for piroxicam ; in vitro transdermal release and permeation studies Piroxicam is a potent synthetic opiate commonly used for surgical analgesia and sedation. It is approximately 200 times more potent than morphine, has a rapid onset (1-2 min), and short duration of action (30-60 min). Due to its potency and quick onset, even a very small dose of fentanyl can lead to sudden death. Morever, the expected concentration range of fentanyl is very low. A concentration of 1-10 ng/mL in plasma is effective therapeutic range for analgesia. Therefore, the detection of lower levels of the compound from analgesia dose is important. In addition, intravenous administraion of fentanyl results in a relatively short half-life, about 3.7 hr in plasma, and simple parenteral administration of fentanyl may not be fully effective, so frequent injections and continuous infusion are required to ensure adequate plasma levels. However, these methods have the disadvantage of potentially causing irreversible damage to nerve or surronding tissue due to fluctuations in concentration and high levels of anesthetic. Additionally, anesthetic delivered in the form of pulse instead of zero-order kinetics may aggravate adverse reactions due to over-dosage. Therefore, a sustained release system might be needed to prolong the action of local anesthetic as well as to avoid the inconvenience of patients and to maintain constant therapeutic levels. The development of long-acting local anesthetics is also needed for postoperative analgesia and control of chronic pain of cancer patients.
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