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ABSTRACT: We developed a pharmacokinetic/pharmacodynamic (PK/PD) model with the value of the plasma ratio of dihydrouracil (UH2)/uracil (Ura), which is a possible surrogate biomarker of hepatic dihydropyrimidine dehydrogenase activity, determined before 5-fluorouracil (5-FU) treatment to simulate the growth of tumors after 5-FU treatment in rats with colorectal cancer (CRC). In the PK/PD model, the value of the elimination rate constant of 5-FU-ke -was estimated using the plasma UH2/Ura ratio observed before 5-FU treatment for simulating PKs of 5-FU and tumor growth. The PK/PD model with plasma UH2/Ura ratio effectively captured the features of tumor growth and the anticancer effect of 5-FU treatment, which provided reliable parameter estimates. In addition to an appropriate dosing regimen, pretherapeutic assessment of the UH2/Ura ratio in the plasma of CRC patients and PK/PD analysis with the plasma UH2/Ura ratio could enable the development of an optimal therapeutic scheme for each patient. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
Journal of Pharmaceutical Sciences 04/2013; · 3.06 Impact Factor
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ABSTRACT: Ritonavir (RTV) is not only an inhibitor but also an immunoreactive inducer of both P-glycoprotein (Pgp) and cytochrome P450 (CYP) 3A in terms of its chronic use. The aim of present study was to test the hypothesis that the power balance between inhibition effects of RTV and induced activities of Pgp and CYP3A depends on the time after last RTV treatment (TimeR) in the chronic use of RTV; rhodamine 123 (Rho) and midazolam (MDZ) were administered at predetermined TimeR to rats pretreated with RTV for 7 days. After oral administration of Rho and MDZ to rats pretreated with RTV for 7 days, the areas under the plasma concentration-time curve of Rho and MDZ were significantly altered depending on TimeR: 1.27-, 0.79-, 0.95-, and 0.11-fold increases over that of the control for Rho at TimeR = 0, 3, 9, and 24 h and 3.12-, 1.50-, 1.27-, and 0.17-fold increases over that of the control for MDZ at TimeR = 0, 3, 9, and 24 h, respectively. These results revealed the presence of the time-dependent interaction of RTV with concomitant drugs in chronic use and should be taken into account in therapeutic strategies for HIV infection. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
Journal of Pharmaceutical Sciences 04/2013; · 3.06 Impact Factor
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ABSTRACT: We investigated the correlation between plasma ratio of dihydrouracil/uracil (UH2/Ura), a possible surrogate biomarker of hepatic dihydropyrimidine dehydrogenase (DPD) activity, and 5-fluorouracil (5-FU) treatment efficacy in rats with colorectal cancer (CRC). 5-FU pharmacokinetic and pharmacodynamic studies were performed using DPD circadian variation in rats with 1,2-dimethylhydrazine-induced CRC. By plotting tumor volume after 5-FU treatment against pre-therapeutic plasma UH2/Ura, we inferred a linear relationship (r(2) = 0.988). 5-FU concentration fluctuations induced by DPD activity variation affected tumor volume. In CRC patients receiving proper dosing regimens, plasma UH2/Ura could be an indirect biomarker for predicting 5-FU treatment efficacy, tumor growth, and 5-FU doses.
Biological & Pharmaceutical Bulletin 04/2013; · 1.66 Impact Factor
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ABSTRACT: Abstract We studied the effects of oxidative stress (OS) on the pharmacokinetics of atazanavir (ATV), particularly the distribution of ATV in the plasma and its metabolism in hepatic microsomes, using a rat model of ferric-nitrilotriacetate-induced OS (OS rats). The areas under the plasma concentration-time curves for intravenous bolus, oral, and intraportal administration of ATV in the OS rats were significantly greater than those in the control rats, whereas blood clearance of ATV after intravenous bolus injection in the OS rats (0.94 ± 0.04 L/h/kg) was approximately half of that in the control rats (2.08 ± 0.20 L/h/kg). Moreover, the intrinsic clearance (CL(int)), which is determined by in vitro metabolic studies using hepatic microsomal fractions of rats, was approximately 43% lower in the OS rats (0.489 ± 0.017 mL/min/mg protein) than in the control rats (0.851 ± 0.004 mL/min/mg protein). ATV concentrations in both the plasma-bound fraction and erythrocytes of the OS rats were significantly greater than those in the control rats. These results suggest that the hepatic metabolism of ATV may be reduced in patients under OS.
Free radical research 01/2013; · 2.22 Impact Factor
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ABSTRACT: To increase the absorbed amount of a drug from dissolving microneedles (DMs), three DM array chips were prepared in which (1) the drug was localized at the acral portion of DMs, (2) the drug was loaded in each whole DM, and (3) the drug was loaded in DMs and the chip. Fluorescein free form (FL) and its sodium salt (FLNa) were used as model drugs. The DM array chip had 15-mm diameter with 225 DMs, each 500-µm long with a 300-µm diameter base. The respective FLNa contents in the three chips were (1) 0.18±0.03, (2) 0.64±0.07, and (3) 10.95±1.07 mg. The FL contents were (1) 0.20±0.01, (2) 0.68±0.03 and (3) 12.47±1.01 mg. The in vitro release of fluorescein from FLNa DMs was faster than that from FL DMs. In vitro permeability experiments showed that (3) produced the greatest increase in the permeability of fluorescein through rat skin, especially in FLNa loaded DMs. In vivo rat absorption study by application of DM array chips to the rat abdominal skin for 6 h demonstrated that the systemically absorbed amount of fluorescein increased from 0.18±0.02 mg, 0.53±0.19 mg, to 5.38±1.99 mg from systems (1) and (2)-(3). By decreasing the application time of DMs to the rat skin, the absorbed amount of fluorescein decreased along with the application time. The physiological state of the skin recovered within 30 min after chip removal. Using a type (3) DM array chip, more than 1.0 mg of water-soluble drug can be delivered to the systemic circulation.
Chemical & pharmaceutical bulletin 01/2013; 61(1):8-15. · 1.70 Impact Factor
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ABSTRACT: To investigate the hepatic dihydropyrimidine dehydrogenase (DPD) activity in colorectal cancer (CRC), which is critically important to create a patient-specific dosing regimen, we performed 5-FU pharmacokinetic studies in 1,2-dimethylhydrazine-induced CRC model rats (CRC rats). After rats received 5-FU intravenous (IV) bolus injections, the area under the plasma concentration-time curve (AUC) and elimination half-life (t (1/2)) in CRC rats (10.02 ± 0.37 μg h mL(-1), 0.30 ± 0.02 h, respectively) were significantly lower than that in control rats (13.46 ± 1.20 μg h mL(-1), 0.52 ± 0.05 h, respectively), whereas total plasma clearance (CL(tot)) in CRC rats (2.01 ± 0.07 L h(-1) kg(-1)) was significantly increased compared with that in control rats (1.54 ± 0.14 L h(-1) kg(-1)). Conversely, the avoidance ratio of the hepatic first-pass effect was approximately 20 % lower than that in control rats. Of interest is that hepatic DPD activity levels and the dihydrouracil-uracil ratio (UH2/Ura ratio) in plasma, which may act as a potential biomarker to evaluate hepatic DPD activity levels, were significantly increased in CRC rats. These results suggest that the decrease of hepatic availability in CRC rats is brought about by the increase in intrinsic clearance induced by the increase in DPD activity, resulting in a decrease in AUC and t (1/2) and an increase in CL(tot) after 5-FU IV bolus injection. Along with a proper dosing regimen for patients with CRC, a hepatic DPD activity monitoring system, such as the determination of UH2/Ura ratio in plasma, is desirable.
European Journal of Drug Metabolism and Pharmacokinetics 11/2012; · 0.36 Impact Factor
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ABSTRACT: Abstract Background: The aim of this report was to develop a dissolving microneedle (DM) application system, where 225-300 insulin-loaded DMs were formed on a chip. After the heat-sealed sheet is removed, the system covered with the press-through package layer is put on the skin. By pressing with the hand, insulin DMs were inserted into the skin. Materials and Methods: Factors affecting the penetration depth of DM were studied using applicator in vitro and in vivo experiments. The penetration depth was determined for rat and human skin. Two-layered DM array chips were prepared to obtain complete absorption of insulin and administered to the rat abdominal skin. Plasma glucose levels were measured for 6 h. By comparing the hypoglycemic effect with that obtained after subcutaneous injection, relative pharmacological availability (RPA) was determined. Results: The penetration depth increased from 21±3 μm to 63±2 μm in proportion to application speed to isolated rat skin, at 0.8-2.2 m/s. Human skin showed similar results in the penetration depth. The in vivo penetration depth was dependent on the force (0.5-2.5 N) and duration (1-10 min), as the secondary application force. The penetration depth was 211±3 μm with a duration of 3 min in the in vivo rat experiment. DM array chips having an insulin-loaded space of 181.2±4.2 and 209±3.9 μm were evaluated in the rat. RPA values of insulin from DMs were 98.1±0.8% and 98.1±3.1%, respectively. Conclusions: These results suggest the usefulness of the two-layered DM application system for the transdermal delivery of insulin.
Diabetes Technology & Therapeutics 10/2012; 14(10):891-9. · 1.93 Impact Factor
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ABSTRACT: Two-layered dissolving microneedles (DMs) containing intermediate-acting insulin, protamine sulfate insulin (PSI), were prepared. Then a pharmacodynamic study was performed to evaluate the prolonged hypoglycemic effects in rats. The DMs were approximately 497±5 μm long, with 303±3 μm diameter at their base. The length of the insulin loaded space was 182±4 μm. PSI contents in DMs were 0.51±0.02 IU. A three-month stability study showed that 99.9±1.4% of PSI was recovered at 4 °C. As the temperature increased to 40 °C, recovery decreased to 97.5±2.0%. PSI was released within 5 min from DMs. Hypoglycemic effects of PSI DMs were evaluated in rats where subcutaneous injection preparations were used as references. Total area above the plasma glucose level (% of the pre-dose level) vs. time curve as an index of hypoglycemic effect was 144.0±16.0% h and 243.3±8.5% h for PSI DMs at 1.46 and 3.28 IU/kg. The relative pharmacologic availability of PSI from DMs were 100.2±9.8% and 91.4±4.1%. No significant difference of hypoglycemic curves was found between DMs and injection solutions, which suggests the usefulness of two-layered DMs of PSI for the displacement therapy of sc injection preparation.
International journal of pharmaceutics 06/2012; 436(1-2):387-93. · 2.96 Impact Factor
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ABSTRACT: The effects of oxidative stress (OS) on the pharmacokinetics of fluvoxamine (FLV), particularly on FLV distribution in the plasma, were studied in ferric-nitrilotriacetate-induced OS rat models (OS rats). The study protocol involved a continuous FLV infusion (25.0 μg/kg/min). The resulting mean plasma FLV concentration measured in steady state OS rats was 0.13 ± 0.01 μg/mL, which was significantly lower than plasma concentrations measured in control rats (0.19 ± 0.01 μg/mL). Moreover, the mean FLV concentration in the OS rat brain (0.51 ± 0.08 μg/g) was determined to be approximately half the concentration in control rat brains (0.95 ± 0.11 μg/g). The FLV concentrations in both the unbound fraction of plasma and erythrocytes of OS rats were significantly greater than that of control rats. These results suggest the potential attenuation of FLV's pharmacological effects in patients under OS.
Free radical research 04/2012; 46(7):831-41. · 2.22 Impact Factor
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ABSTRACT: Antigen-loaded dissolving microneedle array (dMNA) patches were investigated as novel systems for vaccine delivery into the skin, where immuno-competent dendritic cells are densely distributed. We fabricated micron-scale needles arrayed on patches, using chondroitin sulfate mixed with a model antigen, ovalbumin. Insertion of dMNA effectively delivered substantial amounts of ovalbumin into the skin within 3 min and induced robust antigen-specific antibody responses in the sera of mice. The antibody dose-response relationship showed that the efficiency of dMNA patch immunization was comparable to that of conventional intradermal injections. Thus, Antigen-loaded dMNA patches are a promising antigen-delivery system for percutaneous vaccination.
Vaccine 12/2011; 30(6):1191-7. · 3.77 Impact Factor
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ABSTRACT: To elucidate drug lipophilicity effects on the bioavailability (BA) of drugs from skin after administration by dissolving microneedles, nine compounds with different lipophilicity indexes (log p value) were formulated into two-layered dissolving microneedles and administered percutaneously to rat skin: desmopressin (DDAVP), sumatriptan (ST), fluorescein (FL), granisetron (GRN), pindolol (PDL), pravastatin (PRV), rhodamine 123 (Rho), rifampicin (RFP), and salmeterol (SLM). Plasma drug concentrations were measured using liquid chromatography-tandem mass spectrometry and spectrofluorometry. In vivo dissolution and diffusion in both horizontal and vertical directions of FL and RH in the skin were studied using fluorescence microscopy. Respective BAs were 95.1 ± 7.9% (DDAVP), 84.2 ± 2.7% (ST), 82.3 ± 7.2% (FL), 82.7 ± 6.7% (GRN), 71.6 ± 3.8% (PDL), 63.6 ± 7.5% (PRV), 53.7 ± 8.3% (Rho), 46.2 ± 6.1% (RFP), and 38.4 ± 2.7% (SM). BA decreased as the lipophilicity index, log p value, of the drug increased from-1.95 to 1.73. The respective remaining percentages in skin tissue were 1.4 ± 0.7% (DDAVP), 0.9 ± 0.1% (ST), 1.0 ± 0.2% (FL), 3.4 ± 1.2% (GRN), 14.5 ± 3.7% (PDL), 23.4 ± 5.2% (PRV), 32.2 ± 6.0% (Rho), 40.7 ± 4.9% (RFP), and 40.6 ± 5.1% (SLM), dependent on log p. Fluorescence microscopy showed no FL or Rho in skin tissue within 4 and 24 h after administration, respectively. The BA of drugs delivered by dissolving microneedles depends on the drug solubility in the skin epidermis and dermis.
Journal of Pharmaceutical Sciences 11/2011; 101(3):1145-56. · 3.06 Impact Factor
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ABSTRACT: The effect of oxidative stress (OS) on the pharmacokinetics of clomipramine (CPM), particularly addressing the change of CPM distribution to plasma components, was studied in ferric-nitrilotriacetate-induced oxidative-stress model rats (OS rats). First, CPM pharmacokinetic studies in OS rats were performed using CPM continuous infusion (17.5 μg/min/kg). Plasma concentration of CPM at a steady state in OS rats (0.20 ± 0.02 μg/mL) was significantly lower than that in control rats (0.30 ± 0.02 μg/mL). However, no difference was found in the amounts of CPM in the brains of control rats (1.67 ± 0.13 μg/g) and OS rats (1.63 ± 0.09 μg/g). Both of plasma unbound fraction and distribution to erythrocytes in OS rats were significantly higher than those of control rats. These results suggest that the lower CPM concentration in plasma in OS condition does not induce an inferior pharmacological effect.
Drug metabolism letters. 10/2011; 5(4):243-52.
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ABSTRACT: Many clinical reports and trials have suggested that fluvoxamine (FLV) reduces plasma lipoprotein levels. However, few studies have reported the effect of plasma lipoproteins on FLV pharmacokinetics. The aim of the present study was to investigate the affinities of FLV to plasma lipoproteins and the effect of plasma lipoproteins on the biodistribution of FLV using an experimental hyperlipidemic (HL) rat model.
HL rats were prepared by intraperitoneal administration of Poloxamer-407 solution (1.0 g/kg). In vitro protein binding and distribution of FLV in plasma lipoproteins were determined in control and HL rats. In vivo pharmacokinetic study (intravenous administration of FLV, 5.0 mg/kg) and biodistribution analysis for brain and liver at a steady state (infusion, 1.5 mg/kg/hr, 6 hrs) were also performed.
The plasma protein binding of FLV was around 83% and 95% in control and HL rats, respectively, whereas the FLV recoveries in triglyceride-rich lipoprotein fractions were increased in HL. Therefore, the elevation of lipoproteins was likely responsible for the increase in protein binding in HL. After intravenous administration, the area under the plasma concentration vs. time curve (AUC) in HL was 3.9-fold greater than that in control rats, whereas the distribution ratio of FLV plasma concentration to the brain at a steady state was decreased to approximately 20% of that of the control.
FLV has an affinity to plasma lipoproteins, and their elevation might decrease the FLV biodistribution to brain; the plasma lipoprotein levels could not be found to correlate positively with the FLV pharmacokinetic effect in brain, but rather may attenuate it.
Journal of pharmacy & pharmaceutical sciences: a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques 07/2011; 14(3):414-24. · 1.65 Impact Factor
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ABSTRACT: A novel transdermal delivery of sumatriptan (ST) was attempted by application of dissolving microneedle (DM) technology. Dextran DM (d-DM) and hyaluronate DM (h-DM) were prepared by adding ST solution to dextran solution or hyaluronic acid solution. One DM chip, 1.0 × 1.0 cm, contains 100 microneedle arrays in a 10 × 10 matrix. The mean lengths of DMs were 496.6 ± 2.9 μm for h-DM and 494.5 ± 1.3 μm for d-DM. The diameters of the array basement were 295.9 ± 3.9 μm (d-DM) and 291.7 ± 3.0 μm (h-DM), where ST contents were 31.6 ± 4.5 μg and 24.1 ± 0.9 μg. These results suggest that ST was stable in h-DM. Each DM was administered to rat abdominal skin. The maximum plasma ST concentrations, Cmax, and the areas under the plasma ST concentration versus time curves (AUC) were 44.6 ± 4.9 ng/ml and 24.6 ± 3.9 ng · h/ml for h-DM and 38.4 ± 2.7 ng/ml and 14.1 ± 1.5 ng · h/ml for d-DM. The bioavailabilities of ST from DMs were calculated as 100.7 ± 18.8% for h-DM and 93.6 ± 10.2% for d-DM. Good dose dependency was observed on Cmax and AUC. The stability study of ST in DM was performed for 3 months under four different conditions, −80, 4, 23, and 50°C. At the end of incubation period, they were, respectively, 100.0 ± 0.3%, 97.8 ± 0.2%, 98.8 ± 0.2%, and 100.7 ± 0.1%. These suggest the usefulness of DM as a noninvaisive transdermal delivery system of ST to migraine therapy.
Drug Development and Industrial Pharmacy 05/2011; 37(12):1387-93. · 1.49 Impact Factor
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ABSTRACT: This study was undertaken to investigate the effects of hyperlipidaemia on the pharmacokinetics of clomipramine, an antidepressant, particularly addressing the change of clomipramine distribution to plasma components in poloxamer 407-induced hyperlipidaemia model rats.
Clomipramine pharmacokinetic studies in hyperlipidaemic rats were performed with clomipramine continuous infusion. Furthermore, clomipramine protein binding and distribution to the brain and plasma components such as lipoproteins were investigated.
Mean plasma concentration of clomipramine at steady state during continuous infusion (17.5µg/min/kg) in hyperlipidaemic rats (0.45±0.01µg/ml) was significantly higher than that in the control rats (0.30±0.02µg/ml). However, the amount of clomipramine in the brain in hyperlipidaemic rats (0.31±0.06µg/g) was dramatically lower than in the control rats (1.89±0.13µg/g). However, the plasma unbound fraction in hyperlipidaemic rats (0.98±0.05%) was significantly lower than that of the control rats (6.51±0.62%).
Lower distribution to the brain and lower plasma clearance of clomipramine in hyperlipidaemic rats resulted from lower plasma unbound fraction because of higher lipid-rich protein contents in blood. Results of this study provide useful information for dosage adjustment of clomipramine in hyperlipidaemia.
The Journal of pharmacy and pharmacology. 04/2011; 63(4):515-23.
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ABSTRACT: As a percutaneous sustained-release preparation, insulin micropiles (MPs) were prepared with biodegradable polymers poly(lactic acid) (PLA), poly(ϵ-caprolactone) (PCL) and poly(lactic-co-glycolic acid) (PLGA) as the base. The obtained PLA, PCL, and PLGA MPs of which the insulin:polymer ratio was 1:2 were administered to rat skin at 40 IU/kg and hypoglycemic effects measured for 6 days. The order of the hypoglycemic effect was PLA>PCL>PLGA. PLA MP showed the strongest hypoglycemic effect (2 days). The hypoglycemic effect of insulin PLA MP was dependent on the formulation; the order was insulin:PLA (2:1)>insulin:PLA (1:1)>insulin:PLA (1:2). As the ratio of insulin to the polymer base increased, the hypoglycemic effect increased. The area above the plasma glucose levels vs. time curves for 6 days from insulin:PLA (2:1) MPs, 10, 20, 30, and 40 IU/ kg, were 249 ± 108, 2003 ± 379, 3960 ± 794, and 6311 ± 726%·h. A dose-dependent hypoglycemic effect was obtained at 10-40 IU/kg and pharmacological availabilities were 11.1%, 44.5%, 58.6%, and 70%, respectively. Insulin:PLA (2:1) MP showed high plasma insulin level, 86.9-134.7 IU/mL, for 3 days. There was no damage to rat skin. These results suggest the usefulness of insulin:PLA (2:1) MP as a sustained-release percutaneous delivery system for insulin.
Journal of Drug Targeting 04/2011; 19(3):212-8. · 2.70 Impact Factor
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ABSTRACT: The efficiency and usefulness of oral cisplatin using sustained-release cisplatin solid dispersions was studied in tumour-loaded mice.Mice were inoculated intraperitoneally with P815 tumour cells, before treatment with 10 mg kg−1 cisplatin. Cisplatin solid dispersions were suspended in 1% sodium carboxy-methylcellulose and administered according to seven therapeutic schedules. Group A received one dose on day 1; B, daily doses on days 1, 2 and 3; C, daily doses on days 1, 3 and 5; D, daily doses on days 1, 2, 3, 4 and 5; E, daily doses on days 1, 3, 5, 7 and 9; F, daily doses on days 1, 2, 3, 4, 5, 6 and 7; G, daily doses on days 1, 3, 5, 7, 9, 11 and 13. Control mice received a solid dispersion not loaded with cisplatin and reference mice received 10 mg kg−1 cisplatin in solution. Mean survival times were significantly increased in groups D, E, F and G compared with control and reference mice (13.6±0.2, 9.5±0.8, 16.1±0.3; 13.8±0.2, 11.1±0.8, 15.0±0.5; 13.4±0.2, 7.6±0.2, 16.1±0.3; 13.3±0.2, 11.0±0.9, 15.9±0.3 days for control, reference and cisplatin solid dispersion, respectively). Toxicokinetic studies were performed in another three groups of mice receiving 10 mg kg−1 cisplatin solid dispersion daily for five and seven doses and every 2 days for a total of seven doses. The base and the peak serum cisplatin concentrations were measured by atomic absorption and were within the therapeutic range for cisplatin (0.2–1.0 μg mL−1).The results suggest the efficiency and usefulness of oral cisplatin therapy with sustained-release cisplatin solid dispersions in the tumour-transplanted mouse model.
Pharmacy and Pharmacology Communications. 03/2011; 4(12):573 - 577.
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ABSTRACT: The aim of this study is to investigate the feasibility of three-layered particles as a drug delivery system to the lower part of small intestine.
The particle surface and basement layers were made of enteric polymer, Eudragit(®) S100, and water-insoluble polymer, ethylcellulose. Prednisolone (PSL), as a model drug, was sealed with the surface and basement layers. After the administration of the test preparations to the duodenum of rats, blood samples were collected and plasma PSL levels were measured by high-performance liquid chromatography. The retention and transit characteristics of the three-layered particles in rat small intestine were studied by direct observation after abdominal incision up to 8 hours.
Three-layered PSL particles showed C(max) of 0.32 ± 0.07 μg/mL and T(max) at 6 hours, whereas the mean C(max) and T(max) of PSL powder, as a reference preparation, were 0.42 ± 0.03 μg/mL and 1 hour, respectively. With the direct observations, after administration of particles, about 77.5% of them were detected in duodenum at 1 hour, 45% in distal jejunum at 3 hours, and 50% in proximal ileum at 4 hours. Then, they were gradually transferred to the lower part of the small intestine at 5-8 hours time intervals. In comparison with PSL powder, three-layered particles delayed the intestinal transit and released PSL during their passage through the small intestine.
These results suggested that three-layered particles adhered to the gastrointestinal mucosa and sustained the release of drug, resulting in drug delivery to the lower part of gastrointestinal tract.
Drug Development and Industrial Pharmacy 03/2011; 37(3):335-41. · 1.49 Impact Factor
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ABSTRACT: Two-layered dissolving microneedles of which acral portion contained leuprolide acetate (LA) as solid dispersion were prepared with sodium chondroitin sulfate as the base and the systemic absorption efficiency of LA was studied in rats after administration to their abdominal skin. A patch contained 100 dissolving microneedles of which length and basement diameter were 469.8±4.7 μm and 284.5±9.8 μm, where LA content was 14.3±1.6 μg. In vitro dissolution experiment showed that LA was released from dissolving microneedle patch within 3 min. LA was stable in the patch, % recoveries for 3 months were 102.2±1.9-95.3±1.9%. One and half-patch of LA dissolving microneedles were administered to the rat skin and plasma LA concentrations were measured by LC-MS/MS. Plasma LA concentrations increased immediately after administration, and reached to the maximum level at 15 min, where C(max) were 6.0±0.7 and 16.4±0.9 μg/ml, respectively. The AUC were 5.8±0.8 and 14.5±0.4 μg h/ml and BA were 33.8±4.3% and 31.7±0.8%. When LA solution was subcutaneously (s.c.) injected to rats, 50 μg/kg, the BA was 32.0±2.1%. Relative BA of LA from dissolving microneedles against s.c. solution was 105.6±13.5%. The degradation rate of LA in the rat skin tissue homogenate was very fast where the half-life was 16.3±5.7 min. The degradation of LA in the skin tissue was the cause of the low BA of LA after percutaneous administration to rats.
International journal of pharmaceutics 01/2011; 407(1-2):126-31. · 2.96 Impact Factor
