• 약학회지
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• 제41권3호
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• pp.305-311
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• 1997

Sustained release-microspheres and immediate release-pellets were prepared to develop a controlled release multiparticulate system containing both water soluble and insoluble dr ug. Pseudoephedrin.HCl (EPD) and terfenadine (TRF) were used as model drugs, respectively. Sustained release-EPD microspheres were prepared by solvent evaporation method using Eudragit RL or RS as a matrix combined with pH-insensitive film coating. Smaller EPD microspheres were obtained when smaller amount of Eudragit as a matrix material or larger amount of magnesium stearate as a dispersing agent was used. However the obtained microspheres did not show syfficient sustained release characteristics. About 97% of EPD was released after 1 hr irrespective of matrix material used. Subsequent coating of the microspheres with pH-insensitive polymer such as Eudragit RS or ethylcelulose (EC) resulted good sustained in 37.5, 73.3 and 92.0% release of encapsulated EPD in distilled water after 1, 3 abd 7 hr, respectively. It corresponds to mean dissolution time (MDT) of 2.3 hr, which is much larger than that of un-coated EPD microspheres (0.0048 hr). Immediate release TRF pellets were prepared by spherically agglomerated crystallization using Eudragit E as an inert matrix and methylene chloride as a liquid binder. Using Eudragit E alone as a matrix resulted in satisfactory physical properties of the pellets such as sphericity, surface texture and flowability, but led to slower release of TRF from pellets than un-modified TRF powder (MDT of 1.70 vs 1.43 hr in pH 1.2 dissolution medium). Introducing propylene glycol or sodium lauryl sulfate as an emulsifier brought about faster release of TRF from pellets (MDT of 1.14 and 0.95 hr, respectively). In conclusion, microencapsulation by solvent evaporation combined with film coating and spherically agglomerated crystallization were successfully utilized to prepare controlled release multiparticulate system composed of sustained release EPD-microspheres and immediate release TRF pellets.

• Journal of Pharmaceutical Investigation
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• 제27권4호
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• pp.323-329
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• 1997

Ipriflavone is non-hormonal antiosteoporotic drug which inhibits bone resorption by reducing recruitment and/or differentiation of osteoclasts, and stimulates proliferation and differentiation of osteoblast, and also enhances calcitonin secretion in the presence of estrogen. Although some kinds of immediately-released preparation of ipriflavone are available in commercial market, in present study, we tried to formulate sustained-release tablet using coating method with hydrophobic and hydrophilic coating materials. In vitro dissolution test was applied to evaluate sustained-release patterns of several test preparations (Test tablet A, B and C) designed using different preparation method or different compositions. From the results of dissolution test, test tablet A which showed suitable dissolution profile was selected as the candidate of new product. Pharmacokinetic evaluation of test drug, ipriflavone sustained-release tablets, was conducted in 6 beagle dogs weighing $11.5{\pm}0.5\;Kg$ compared with $Theobon^{\circledR}$ tablet, immediately-released tablet (Kukjae Pharm. Co.) as reference drug. Two products were randomly administered to 6 beagle dogs, and after 1 week, cross-over study was conducted. From the present study, AUC and $T_{max}$ of test product were significantly different from those of reference product (p<0.05), respectively$(AUC\;:\;3646.28{\pm}472.56\;vs\;3646.28{\pm}472.56\;ng{\cdot}hr/ml,\;T_{max}\;:\;4.33{\pm}1.03\;vs\;1.42{\pm}0.38\;hr)$. But $C_{max}$ was not significantly different between two products (p>0.05) $(\;512.52{\pm}48.18\;vs\;443.97{\pm}140.53\;ng/ml)$. From the results of pharmacokinetic evaluations, it was noted that absorption amount of test product was increased, but absorption rate was delayed and $C_{max}$ of two products were not changed. And it was concluded that redesign of the sustained-release preparation which has a lower content of iprifavone rather than test tablet A must be considered.

• Journal of Pharmaceutical Investigation
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• 제35권6호
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• pp.453-460
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• 2005

4-Aminopyridine (AP) is a potassium channel blocker used in the treatment of neurological disorders such as multiple sclerosis and Alzheimer disease. AP‘s window of therapeutic effect appears to correlate with its plasma halflife (3.5 hours). It demonstrates pH-dependent solubility because of a weakly basic drug. In addition, the resulting release from conventional matrix tablets decreases with increasing pH-milieu of the gastrointestinal tract. The aim of this study is to design sustained release matrix tablet containing AP, overcoming this problem. $Eudragit^{\circledR}$ L 100 (EuL) and sodium alginate were used in an effort to achieve pH independent drug release. The effect of sodium alginate and EuL on drug release from matrix tablet was investigated. The drug release behavior from the different tablets was analyzed by $t_{20%},\;t_{40%},\;t_{60%}$, The exponential diffusion coefficient n, kinetic constant K were calculated according to the Korsmeyer-Peppas equation. The drug release from matrix tablets prepared with sodium alginate was decreased with increasing the content of sodium alginate in pH 7.4 while there is no significant difference in pH 1.2. The exponent n values were determined to be approximately 0.5 and 0.8 respectively, in both pH 1.2 and 7.4. These values indicate diffusion-based anomalous mechanism and erosion-based anomalous mechanism, respectively. The drug release from sodium alginate matrix tablets prepared with solid dispersion of EuL containing drug showed a slow drug release in an acidic medium and a more fast drug release in phosphate medium, compared with sodium alginate matrix tablets prepared with physical mixture. These results may be attributed to the gel forming ability of sodium alginate and pH dependent solubility of EuL. Therefore, sustained-release AP matrix tablets using sodium alginate and EuL were successfully prepared.

• Journal of Pharmaceutical Investigation
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• 제25권2호
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• pp.109-116
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• 1995

For the administration of narcotic antagonist with short half-life and low patient compliance, the sustained release system using biodegradable matrix is effective. Polyphosphazenes are of considerable interest as biodegradable matrix systems for controlled release of drugs. In this study, biodegradable polyphosphazenes available for the sustained release implantable device were synthesized, and their application was examined. Poly[dichlorophosphazene] was synthesized by solution polymerization method and confirmed with IR spectrum. Poly[bis(ethyl glycinate) phosphazene] and poly[ (diethyl glutamate)-co-(ethyl glycinate)phosphazene] were then produced by substitution of amino acid alkyl esters for chloride side groups. Using these polymers, the implantable devices of 1 mm thickness and $10{\times}10\;mm$ size containing naloxone hydrochloride were prepared and their release and degradation profiles were measured. In the case of poly[bis(ethyl glycinate)phosphazene] with swelling characteristics, degradation rate was slower than the release rate, showing that the release rate is partly dependent on the swelling rate. In contrast, the degradation rate of polyl[(diethyl glutamate)-co-(ethyl glycinate)phosphazene] matrix was identical with release rate of naloxone hydrochloride. On the basis of these results, it is expected that these polymers can be applied to sustained release implantable systems delivering narcotic antagonist.

• 한국생물공학회:학술대회논문집
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• 한국생물공학회 2000년도 춘계학술발표대회
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• pp.541-545
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• 2000

For the sustained release formulation of recombinant human growth hormone (rhGH), dissociable rhGH aggregates were microencapsulated within poly(D,L-lactic-co-glycolic acid) [PLGA] microparticles. rhGH aggregates with 2 - 3 m Particle diameter were first produced by adding a small volume of aqueous rhGH solution into a partially water miscible organic solvent phase(ethyl acetate) containing PLGA. These rhGH aggregates were then microencapsulated within PLGA polymer phase by extracting ethyl acetate into an aqueous phase pre-saturated with ethyl acetate. The resultant microparticles were 2 - 3 m in diameter similar to the size of rhGH aggregates, suggesting that PLGA polymer was coated around the protein aggregates. Release profiles of rhGH from these microparticles were greatly affected by changing the volume of the incubation medium. The release rhGH species consisted of mostly monomeric form with having a correct conformation. This study reveals that sustained rhGH release could be achieved by microencapsulating reversibly dissociable protein aggregates within biodegradable polymers.

• Asian Pacific Journal of Cancer Prevention
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• 제15권1호
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• pp.407-411
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• 2014

Objective: To observe local and systemic toxicity after sustained-release 5-fluorouracil (5-Fu) implantation in canine peritoneum and para-aortic abdominalis and the changes of drug concentration in the local implanted tissue with time. Methods: 300 mg sustained-release 5-Fu was implanted into canine peritoneum and para-aorta abdominalis. Samples were taken 3, 5, 7 and 10 days after implantation for assessment of changes and systemic reactions. High performance liquid chromatography was applied to detect the drug concentrations of peritoneal tissue at different distances from the implanted site, lymphatic tissue of para-aortic abdominalis, peripheral blood and portal venous blood. Results: 10 days after implantation, the drug concentrations in the peritoneum, lymphatic tissue and portal vein remained relatively high within 5 cm of the implanted site. There appeared inflammatory reaction in the local implanted tissue, but no visible pathological changes such as cell degeneration and necrosis, and systemic reaction like anorexia, nausea, vomiting and fever. Conclusions: Sustained-release 5-Fu implantation in canine peritoneum and para-aortic abdominalis can maintain a relatively high tumour-inhibiting concentration for a longer time in the local implanted area and portal vein, and has mild local and systemic reactions. Besides, it is safe and effective to prevent or treat recurrence of gastrointestinal tumours and liver metastasis.

• Biomolecules & Therapeutics
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• 제22권2호
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• pp.161-165
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• 2014

The main purpose of this study was to develop a novel, in situ gel system for sustained delivery of ranitidine hydrochloride. Ranitidine in situ gels at 0.2%, 0.5%, and 1.0% gellan gum concentration (w/v) were prepared, respectively, and characterized in terms of preparation, viscosity and in vitro release. The viscosity of the gellan gum formulations in solution increased with increasing concentrations of gellan gum. In vitro study showed that the release of ranitidine from these gels was characterized by an initial phase of high release (burst effect) and translated to the second phase of moderate release. Single photon emission computing tomography technique was used to evaluate the stomach residence time of gel containing $^{99m}Tc$ tracer. The animal experiment suggested in situ gel had feasibility of forming gels in stomach and sustained the ranitidine release from the gels over the period of at least 8 h. In conclusion, the in situ gel system is a promising approach for the oral delivery of ranitidine for the therapeutic effects improvement.

• Archives of Pharmacal Research
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• 제20권6호
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• pp.555-559
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• 1997

The three different batches of an oral sustained release melatonin (MT) delivery system were prepared by aqueous-based fluid-bed coating of the sugar spheres for the evaluation of in vitro release characteristics and plasma concentration profiles in human subjects. The MT contents in 20% coated sugar spheres of three batches (B1, B2 and B3) were $3.3{\pm}0.08$, $2.4{\pm}0.1$ and $2.5{\pm}0.13$ mg per gram of coated sugar spheres, respectively. The release profiles of three different batches had a very similar fashion. However, the release profiles of three different batches had a very similar fashion. However, the release half-lives $(T_{50%})$ of MT from B1, B2 and B3 was $3.70{\pm}0.2$, $5.2{\pm}0.2$ and $4.9{\pm}0.07h$, respectively. Plasma concentration profiles of sustained release 0.2mg melatonin-loaded sugar spheres containing 10% immediate release melatonin in gelatin capsules (B1 and B2) were then evaluated in human subjects. The in vivo plasma concentration profies of the two batches (B1 and B2) were very similar each other and located between the physiological endogenous ranges. The time to reach the peak concentration $(T_max)$ was more advanced in case of B1 when compared to B2. However, there was no statistically significant difference in the maximum concentration $(C_max)$ and the area under the curve (AUC) between B1 and B2. The AUC of melatonin-loaded sugar spheres containing 10% and 20% immediate release MT in human subjects had a good linearity between dose and AUC, regardless of the fraction of immediate release MT, indicating the first order elimination process of MT within these doses. The current oral sustained release MT delivery system may be utilized to treat circadian rhythm disorders if it is proven to be more clinically useful when compared to immediate release MT.

• 약학회지
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• 제15권3_4호
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• pp.79-82
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• 1971

In order to compare the iron concentrations of the marketed ferruginous hematinics with the sustained-releasedosage forms and to prepare the good hemantinic which can be absorbed effectively without forming "iron block" in the gastrointestinal tract, gelatinized micropellets containing medicament were prepared and hardened in 10% formalin-isopropanol in the time of 72 hours. These micropellets were digested with artificial gastric juice and plotted a curve of released iron concentration. As a result, it is found that gelatinized micropellets sustained-release dosage form is an excellent ferruginous hemantinic and it is shown that several marketed preparations can be improved in their hemantinic actions by forming the sustained-release dosage.se dosage.

• Journal of Pharmaceutical Investigation
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• 제26권2호
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• pp.119-124
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• 1996

To develop oral controlled release dosage forms, ionic interactions between polymers and drugs were evaluated. Hydroxypropylmethyl cellulose and carboxymethylene were used as model nonionic and ionic polymers, respectively. 5-fluorouracil, propranolol-HCl and sodium salicylate were selected as model nonionic, cationic and anionic, respectively. Polymer-drug mixtures were compressed into tablets and drug release kinetics from these tablets were determined. Drug release from the tablets made of the nonionic polymer was not affected by the charge of drugs, rather, was regulated by the solubility of drugs in different pH releasing media. However, drug release kinetics were significantly affected when drug-polymer ionic interactions exist. Enhanced drug release was observed from anionic drug-anionic polymer tablets due to ionic repulsion, whereas drug release was retarded in cationic drug-anionic polymer tablets owing to ionic attractive force. Therefore, the results suggested that the polymer-drug interactions are important factors in designing controlled release dosage forms.