• Journal of Korean Neurosurgical Society
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• v.58 no.1
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• pp.1-8
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• 2015

Treatment of Leptomeningeal carcinomatosis (LMC) from solid cancers has not advanced noticeably since the introduction of intra-cerebrospinal fluid (CSF) chemotherapy in the 1970's. The marginal survival benefit and difficulty of intrathecal chemotherapy injection has hindered its wide spread use. Even after the introduction of intraventricular chemotherapy with Ommaya reservoir, frequent development of CSF flow disturbance, manifested as increased intracranial pressure (ICP), made injected drug to be distributed unevenly and thus, the therapy became ineffective. Systemic chemotherapy for LMC has been limited as effective CSF concentration can hardly be achieved except high dose methotrexate (MTX) intravenous administration. However, the introduction of small molecular weight target inhibitors for primary cancer treatment has changed the old concept of 'blood-brain barrier' as the ultimate barrier to systemically administered drugs. Conventional oral administration achieves an effective concentration at the nanomolar level. Furthermore, many studies report that a combined treatment of target inhibitor and intra-CSF chemotherapy significantly prolongs patient survival. Ventriculolumbar perfusion (VLP) chemotherapy has sought to increase drug delivery to the subarachnoid CSF space even in patients with disturbed CSF flow. Recently authors performed phase 1 and 2 clinical trial of VLP chemotherapy with MTX, and 3/4th of patients with increased ICP got controlled ICP and the survival was prolonged. Further trials are required with newly available drugs for CSF chemotherapy. Additionally, new LMC biologic/pharmacodynamic markers for early diagnosis and monitoring of the treatment response are to be identified with the help of advanced molecular biology techniques.

• The Korean Journal of Pain
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• v.29 no.3
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• pp.153-157
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• 2016

Tapentadol is a novel oral analgesic with a dual mode of action as an agonist of the ${\mu}$-opioid receptor (MOR), and as a norepinephrine reuptake inhibitor (NRI) all in a single molecule. Immediate release (IR) tapentadol shows its analgesic effect quickly, at around 30 minutes. Its MOR agonistic action produces acute nociceptive pain relief; its role as an NRI brings about chronic neuropathic pain relief. Absorption is rapid, with a mean maximal serum concentration at 1.25-1.5 h after oral intake. It is present primarily in the form of conjugated metabolites after glucuronidation, and excretes rapidly and completely via the kidneys. The most common adverse reactions are nausea, dizziness, vomiting, and somnolence. Constipation is more common in use of the ER formulation. Precautions against concomitant use of central nervous system depressants, including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol, or use of tapentadol within 14 days of the cessation of monoamine oxidase inhibitors, are advised. The safety and efficacy have not been established for use during pregnancy, labor, and delivery, or for nursing mothers, pediatric patients less than 18 years of age, and cases of severe renal impairment and severe hepatic impairment. The major concerns for tapentadol are abuse, addiction, seeking behavior, withdrawal, and physical dependence. The presumed problem for use of tapentadol is to control the ratio of MOR agonist and NRI. In conclusion, tapentadol produces both nociceptive and neuropathic pain relief, but with worries about abuse and dependence.

• Polymer(Korea)
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• v.32 no.2
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• pp.103-108
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• 2008

Osmotic pellet, which consisted of water-swellable seed layer, drug layer, and porous membrane layer, has been widely utilized in oral drug delivery system. In this work, we describe the preparation of osmotic pellet with nifedipine as model drug and a mixture of cellulose acetate (CA) and Eudragit RS as membrane layer, and then examined the drug release behavior on the variation of the thickness change of membrane layer (CA and Eudragit RS) and release media. Furthermore, we examined the nifedipine release behavior using sodium alginate as a potential membrane candidate. Osmotic pellet was obtained in the quantitative yield by fluidized bed coater. Osmotic pellet exhibited the round morphology and the size ranging $1500{\sim}1700{\mu}m$ in SEM. The nifedipine release decreased as the thickness of membrane layer (CA and Eudragit RS) increased. In addition, it observed that there is difference of release amount in between intestinal juice (pH 6.8) and gastric juice (pH 1.2). In the case of osmotic pellet coated with sodium alginate, nifedipine release behavior depended on the crosslinking of sodium alginate layer. In conclusion, we found that various membrane layers could control the release amount of nifedipine.

• Journal of Pharmaceutical Investigation
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• v.37 no.3
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• pp.193-196
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• 2007

This study aimed to evaluate and develop $Eudragit^{(R)}$-coated pellets based on the dissolution using the paddle method. As coating materials, two types of $Eudragit^{(R)}$ were applied to obtain either sustained release form or fast released form. The dissolution test was carried out in phosphate buffer solution (pH 6.5) at $37^{\circ}C$, 100 rpm. In order to develop a sustained release preparation containing felodipine, a comparative dissolution study was done using commercial product as a control. The dissolution at 30 min of felodipine from $Eudragit^{(R)}$ RS or RL-coated pellets were 0.96% and 99.65, respectively. The weight ratio of $Eudragit^{(R)}$ RL pellets to RS pellets altered the dissolution rate, but did not optimize the dissolution rate. However, the sustained dissolution of felodipine from pellets was optimized by varying the coating ratios of $Eudragit^{(R)}$ RS. It is suggested that the coating ratio of pellets is the main factor which controls dissolution rate. Taken together, $Eudragit^{(R)}$ RS 30D-coated pellets showed the most comparable dissolution rate pattern to commercial product, $Splendil^{(R)}$. This sustained release pellets for oral delivery system of felodipine was simply manufactured, and drug release behavior was highly reproducible.

• Journal of Pharmaceutical Investigation
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• v.25 no.4
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• pp.353-363
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• 1995

The purpose of this study was to investigate the intestinal and nasal absorption enhancement of cefotaxime (CTX) by ion-pairing with counterions and to design an effective oral and intranasal drug delivery system for antibiotics. Counterions for absorption promotion were cationic surfactants [cetylpyridinium chloride (CP), cetrimide (CT) and benzalkonium chloride (BA)]. In the presence of counterions, the apparent partition coefficient of cefotaxime was increased depending on the molar concentration of the counterions. Anion interference was observed for ion-pairing of cefotaxime with counterions because of the counterbalance between an anion and counterions. The present study employed the in situ simultaneous nasal and intestinal perfusion technique in rats. The apparent permeabilities $(P_{app})$ of cefotaxime were $1.43{\pm}0.04{\times}10^{-5}\;cm/sec(mean{\pm}S.E)$ in the nasal cavity and 0 in the jejunum, respectively, which indicated that the intrinsic absorptivity of cefotaxime was greater in the nasal cavity than in the jejunum. When ionupairing formers were used, the decreasing order of apparent cefotaxime permeability $(P_{app},\;10^{-5}\;cm/sec)$, corrected for surface area of absorption, was as followings: $BA\;(7.50{\pm}0.36)\;>\;CT\;(4.92{\pm}0.24)\;>\;CP\;(3.01{\pm}0.17)$ in the jejunum and $BA\;(22.31{\pm}1.36)\;>\;CP\;(18.24{\pm}0.81)\;>\;CT \;(16.22{\pm}1.87)$ in the nasal cavity. The increase in permeability of cefotaxime was about 13-fold in the rat nasal cavity and was marked in the rat jejunum for ion-pairing with counterions as compared to those without ion-pairing. The damages of jejunal and nasal mucosal membrane by counterions were observed within approximately 2hrs after removal of ion-pair of cefotaxime with counterions from the nasal cavity and jejunum. These results suggest that CP can be used as an ion-pairing former in the jejunum and CP and CT can be used as ion-pairing formers in the nasal cavity for cefotaxime, as well as for poorly absorbed drugs with a negative charge due to ionization.

• Journal of Pharmaceutical Investigation
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• v.21 no.4
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• pp.215-222
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• 1991

The absorption characteristics of itraconazole, which is an antifungal agent, from intestinal segments in the anesthetized rat i1l situ were investigated in order to design an effective oral drug delivery system. The pH-solubility profile of itraconazole, the rate and extent of absorption of itraconazole, the optimal absorption site(s) of itraconazole and the absorption enhancing effect of sodium cholate on itraconazole were examined in the present study. In situ single-pass perfusion method and recirculating perfusion technique using duodenum(D), jejunum(J) and ileum(I) were employed for the calculation of apparent permeability(Pe) and apparent first-order rate constant(Kobs). respectively. The results of this study were as follows; (1) Itraconazole showed appreciable aqueous solubility only at pH values of below 2.0. (2) pe(cm/sec) decreased in the following order: $D(10.24{\pm}1.78{\times}10^{-4})>J(8.86{\pm}0.79{\times}10^{-4})>I(3.78{\pm}0.13 X 10^{-4})$. (3) $Kobs(min^{-1})$ decreased in the following order: $J(17.12{\pm}3.19{\times}10^{-3})>D(13.37{\pm}0.6{\times}10^{-3})>I(11.05{\pm}0.91{\times}10^{-3})$. (4) The solubility of itraconazole markedly increased with the increase of the concentration of sodium cholate. (5) The addition of 10 mM sodium cholate significantly increased the apparent first-order rate constant of itraconazole in the ileum by a factor of 6.8.

• YAKHAK HOEJI
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• v.44 no.5
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• pp.440-447
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• 2000

Microspheres of felodipine, which is one of the calcium channel blocker using a mixture of Eudragi $t^{R}$ RL, L, E, and cellulose on the base of Eudragi $t^{R}$ RS were investigated. Cremopho $r^{R}$ was added to each preparation of polymers in order to increase the release of felodipine from microspheres. Felodipine-loaded microspheres were prepared by a solvent evaporation method, which is based on dispersion of methylene chloride containing felodipine and polymers in 0.5 w/v % polyvinyl alcohol solution. The average diameter based on the size distribution of the felodipine-loaded microspheres was observed to be ca. 40-55 ${\mu}{\textrm}{m}$. A good and smooth surface were showed in all types of the microspheres. The amount of felodipine loaded was over 90 w/w % in all types of microspheres. The dissolution profiles of felodipine from microspheres were similar with each type of polymer, and about a 60 w/w % of the total amount of felodipine loaded to microsphere was released within 7 hours. Dissolution rate of felodipine from the microsphere was increased by addition of Cremophor. After oral administration of the felodipine-loaded microspheres in PVA solution and felodipine alone in PEG solution to rats, respectively, the pharmacokinetic study revealed that the Tmax values of the microspheres were observed in the range of 0.67~l.0 hr while that of the felodipine solution was obtained 0.33 hr. In addition, the AUC of the microspheres at 0 to 7 hr was remarkably increased in comparison to that of felodipine solution. These results revealed that the microspheres based on Eudragit RS could be a good candidate for the controlled release drug delivery system for felodipine.e.e.e.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.14
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• pp.5681-5686
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• 2015

Background: Pancreatic cancer ranks fourth in deaths caused by cancers throughout the world. Gemcitabine chemotherapy is the primary method of treatment of advanced pancreatic cancer, and in asco2014, it is still firstline chemotherapy. Howeve,r gemcitabine+fluorouracil regimens are also licensed and widely used worldwide. Clinical trials are the best way to evaluate drug efficacy. In this study, we performed a systematic review and a meta-analysis of randomized controlled trials (RCTs) to assess whether gemcitabine+fluoropyrimidine combination therapy improves the prognosis of unresectable pancreatic cancer compared with gemcitabine treatment alone. Materials and Methods: A quantitative up-to-date meta-analysis was undertaken to investigate the efficacy of gemcitabine-based combination treatment compared with gemcitabine monotherapy for locally advanced or metastatic pancreatic cancer. Inclusion was limited to high-quality randomized clinical trials. Results: A total of 12 studies were included in the present analysis, with a total of 3,038 patients recruited. The studies were divided into three subgroups including 5-FU / CAP / S-1 combined with gemcitabine. For the primary endpoint of overall survival (OS), gemcitabine-based combination therapy demonstrated significantly better outcome (HR, 0.88; 95% CI, 0.81-0.95) than gemcitabine monotherapy. The analysis of progression free survival (PFS) also provided a significant result for the combined therapy in a total of 8 trials (2,130 patients) (HR, 0.74; 95% CI, 0.63-0.86). With subgroup analysis according to the method of dosing delivery, we found that in the injection group with 3 trials (889 patients), a negative result was found (HR, 0.93; 95% CI, 0.77-1.12); while a positive result was observed in the oral group with 9 trials (2,149 patients) (HR, 0.87; 95% CI, 0.80-0.95). Conclusions: Gemcitabine combination therapy provides a modest improvement of survival, but is associated with more toxicity compared with gemcitabine monotherapy.