Pharmacokinetic of Behaviors Transdermal Delivery and Oral Administration of Cyclosporin A Preparations in Mice
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The study was to investigate the pharmacokinetic behaviors of cyclosporin A in mice by transdermal delivery of flexible liposomes and oral administration of the marketed preparation. Time courses of drug concentration in blood, kidney and skin were determined after application of flexible liposomes onto the mice skin non-occlusively. Pharmacokinetic behaviors were compared with those in oral administration of Sandimmun Neoral ○R . The relative bioavailability of transdermal delivery versus oral administration was (82.51±5.45)%. The ratio of AUC in kidney was (150.6±15.62)%. Flexible liposomes deposited much more drug in skin than Sandimmun Neoral ○R did. Results showed that flexible liposomes can transport cyclosporin A through mouse skin efficiently and drug tended to be accumulated in tissues rich of fat, like kidney and skin.Cite
Pharmacokinetic Model Analysis of Supralingual, Oral and Intravenous Deliveries of Mycophenolic Acid
Mycophenolic acid (MPA) is commonly used for organ rejection prophylaxis via oral administration in the clinic. Recent studies have shown that MPA also has anticancer activities. To explore new therapeutic options for oral precancerous/cancerous lesions, MPA was designed to release topically on the dorsal tongue surface via a mucoadhesive patch. The objective of this study was to establish the pharmacokinetic (PK) and tongue tissue distribution of mucoadhesive MPA patch formulation after supralingual administration in rats and also compare the PK differences between oral, intravenous, and supralingual administration of MPA. Blood samples were collected from Sprague Dawley rats before and after a single intravenous bolus injection, a single oral dose, or a mucoadhesive patch administration on the dorsal tongue surface for 4 h, all with a dose of 0.5 mg/kg of MPA. Plots of MPA plasma concentration versus time were obtained. As multiple peaks were found in all three curves, the enterohepatic recycling (EHR) model in the Phoenix software was adapted to describe their PK parameters with an individual PK analysis method. The mean half-lives of intravenous and oral administrations were 10.5 h and 7.4 h, respectively. The estimated bioavailability after oral and supralingual administration was 72.4% and 7.6%, respectively. There was a 0.5 h lag-time presented after supralingual administration. The results suggest that the systemic plasma MPA concentrations were much lower in rats receiving supralingual administration compared to those receiving doses from the other two routes, and the amount of MPA accumulated in the tongue after patch application showed a sustained drug release pattern. Studies on the dynamic of drug retention in the tongue after supralingual administration showed that ~3.8% of the dose was accumulated inside of tongue right after the patch removal, ~0.11% of the dose remained after 20 h, and ~20.6% of MPA was not released from the patches 4 h after application. The data demonstrate that supralingual application of an MPA patch can deliver a high amount of drug at the site of administration with little systemic circulation exposure, hence lowering the potential gastrointestinal side effects associated with oral administration. Thus, supralingual administration is a potential alternative route for treating oral lesions.
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Nausea and vomiting are some of the major side effects caused by certain drug therapies, e.g. chemotherapy, radiotherapy and general anesthesia. Because of the nature of the symptoms, oral delivery is inappropriate, while intravenous administration may be unpractical. The aim of the present study was to develop a transdermal gel (2% Klucel®) for ondansetron, a first line 5-HT3-receptor-antagonist antiemetic. The effects of the penetration enhancer camphor and isopropyl-myristate (IPM) were first investigated in-vitro using modified Franz diffusion-cells and then tested in-vivo in a rabbit model by measuring skin and plasma concentrations. Since a disadvantage of transdermal delivery is a prolonged lag-time, the effect of skin treatment with a micro-needle roller was tested. The in-vitro permeation studies through excised porcine ear skin showed that the presence of 2.5% camphor or IPM increased steady state flux by 1.2- and 2.5-fold, respectively, compared to the control gel. Ondansetron was not detectable in either skin or plasma following in-vivo application of the base-gel, whereas the camphor gel and IPM gel delivered 20 and 81 µg/cm2 of ondansetron, respectively. Microporation led to an increase in plasma Cmax and AUC by 10.47 ± 1.68-fold and 9.31 ± 4.91-fold, respectively, for the camphor gel, and by 2.31 ± 0.53-fold and 1.59 ± 0.38-fold, respectively for the IPM gel. In conclusion, the 2.5% IPM gel demonstrated optimal in-vivo transdermal flux. Skin pretreatment with a micro-needle roller slightly improved the delivery of the IPM gel, whereas dramatically increased the transdermal delivery of the camphor gel.
Ondansetron
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Nephrotoxicity
PLGA
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The purpose of this study was to evaluate the effect of absorption enhancer on in-vivo transdermal absorption of cyclosporin using intradermal microdialysis in rats. Cyclosporin oily solutions (0.5, 2, 8% w/v) were prepared from Sandimmun (10% w/v oily oral preparation of cyclosporin) by diluting with olive oil. 1-[2-(Decylthio)ethyl] azacyclopentan-2-one (HPE-101) and glycerin were added to the cyclosporin formulation as an absorption enhancer at various concentrations between 1 and 20%. These formulations were applied to the shaved abdomen of rats treated with intradermal microdialysis at a flow rate of 2.5 microL min-1 for 6 h. Cyclosporin was immediately detected and attained a plateau in the dermal dialysate after topical application of cyclosporin oily solution alone. Cyclosporin levels in the dialysate increased with increasing cyclosporin concentrations in the formulation from 0.5 to 8% (w/v). HPE-101 did not influence cyclosporin absorption at concentrations less than 6% (w/v). Addition of 10% (w/v) HPE-101 significantly enhanced an apparent absorption rate of cyclosporin by 4.9 times. However, 20% (w/v) HPE-101 did not show the enhancing activity. On the other hand, addition of glycerin at concentrations of 6, 10, and 20% (v/v) significantly enhanced an apparent absorption rate of cyclosporin by 3.0, 6.4, and 6.9 times, respectively. The time lag for cyclosporin absorption was less than 0.21 h in all tested cases. This microdialysis study shows that glycerin is a suitable enhancer for improving the in-vivo cyclosporin absorption from the skin.
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Abstract: Purpose: The long term oral therapy of vildagliptin is associated with potential hepatotoxicity and low patient compliance. This study aims at development of a drug in adhesive transdermal patch system of vildagliptin using pressure sensitive acrylic polymers and compare the pharmacokinetics with oral therapy. Methods: The prospective of different chemical enhancers in improving the transport of vildagliptin was assessed ex vivo. In vivo permeation studies in rats were performed using patch system contain sodium lauryl sulfate as enhancer. Results: Drug solubility varied among adhesive bases tested and maximum value (15% w/w) observed with Duro-Tak 87-2510. Incorporation of chemical agents significantly improved the permeation of vildagliptin, but not to the same extent. The highest flux value of vildagliptin was obtained by the addition of sodium lauryl sulfate (22.96 ± 3.58 μg/cm2/h; P<0.0001), which is ~4 folds higher as compared to control. Pharmacokinetic profiles of vildagliptin were different for transdermal and oral delivery with significantly high bioavailability by transdermal delivery. The AUC0-α in transdermal delivery (1018.43 ± 79.56 ng.h/mL) was ~14 folds higher (P<0.0001) as compared to oral administration. Conclusion: The current study concludes that the fabricated drug in adhesive transdermal system could be employed for the effective delivery of vildagliptin. Key words: Transdermal, Adhesive, Vildagliptin, Enhancer, Flux, Pharmacokinetics. Downloads PDF (PDF, 730.34 KB)
Vildagliptin
Transdermal patch
Lornoxicam
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The objective of this study was to investigate the effect of liposomes on the absorption of water-soluble active pharmaceutical ingredients. Salbutamol sulfate (SBS) has been widely used for treatment of bronchospasm in conditions such as asthma. Using SBS as the model drug in this study, we developed SBS-loaded liposomes for oral administration and explored the relationship between their bioavailability and anti-asthmatic efficacy. SBS was entrapped in liposomes with encapsulation efficiency as high as 70%. The in vitro transport profile of SBS across a dialysis membrane for liposome suspension was compared with that for free SBS solution. Oral administration of liposomes labeled with the fluorescent dye 1,1'-dioctadecyltetramethyl indotricarbocyanine iodide (DiR) in a mouse model was assessed by a small animal imaging system. Pharmacokinetic and pharmacodynamic studies on SBS liposome suspension and free SBS solution were performed using animal models via oral administration. The results showed that liposomes could sustain the release of SBS in vitro and decrease the transport rate of SBS across the dialysis membrane. In vivo fluorescence imaging analysis demonstrated DiR liposome distribution in mouse stomach for at least 24 hr. The mean residence time of SBS from liposomes was found to be longer than that of free SBS, suggesting that the relative bioavailability of SBS was higher when liposome delivery was used. The pharmacokinetic data also showed that the drug absorption rate was relatively slower for treatment with liposomal SBS when compared to free SBS. Moreover, SBS liposome suspension was shown to give a prolonged anti-asthmatic effect after oral administration when compared to free SBS solution. Overall, this study demonstrated that use of liposomes as delivery vehicles for sustained drug release and controlled absorption could be a promising approach for improving the therapeutic potency of active pharmaceutical ingredients. Keywords: Liposomes, pharmacodynamic, pharmacokinetic, oral delivery, salbutamol sulfate.
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Objective: To develop acrylate based transdermal drug delivery system (TDDS) for glibenclamide and evaluate it for its pharmacodynamic performance in male Wistar rats.
Methods: The drug embedded in a polymeric matrix of polymethyl methacrylate and ethylcellulose was evaluated for its hypoglycemic activity in normal and streptozotocin induced diabetic rats in comparison with its oral therapy. A glucose tolerance test (GTT) was conducted in oral, TDDS and control group.
Results: TDDS significantly sustained the hypoglycemic activity for 24 hrs in normal rats when compared to oral administration where the effect declined after 8 hrs. In diabetic rats, normoglycemic levels were maintained for a period of 24 hrs after transdermal delivery, an effect comparable to that of oral glibenclamide. The GTT curve was inhibited in both the groups. However, the reduction was slow and sustained in case of TDDS when compared to oral administration where significant hypoglycemic response was observed in all the three studies performed.
Conclusion: The transdermal system is effective in preventing the frequent hypoglycemic episodes encountered after oral glibenclamide administration.
Pharmacodynamics
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Objective: To evaluate the in-vivo performance of orally and transdermally delivered diltiazem hydrochloride in rabbits.
Methods: Transdermal patches of diltiazem hydrochloride (DLT) were formulated employing ethyl cellulose and polyvinylpyrrolidone as film formers. The pharmacodynamic and pharmacokinetic performance of diltiazem hydrochloride after transdermal administration was compared with that of oral administration. This study was carried out in a randomized cross over design in male New Zealand albino rabbits.
Results: The pharmacokinetic parameters such as maximum serum concentration (C max ), time for peak serum concentration (t max ), mean residence time (MRT) and area under the curve (AUC0-() were significantly (p <0.01) different following transdermal administration compared to oral administration. The terminal elimination half life of transdermally delivered diltiazem was found to similar that of oral administration. A sustained therapeutic activity was observed over a study period of 24 hrs after transdermal administration compared to oral administration. The skin irritation studies indicated that there is no recognisable changes on skin surface after the removal of polymeric films.
Conclusions: The relative bioavailability of diltiazem hydrochloride and its therapeutic activity were increased about five fold after transdermal administration compared to oral route.
Diltiazem hydrochloride
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Monolithic transdermal therapeutic systems (TTS) were developed for sustained antihypertensive effect of losartan potassium using the polymers Eudragit E 100 and polyvinyl pyrrolidone VA 64. The developed formulations (polymeric films) were evaluated for physical characteristics, ex vivo (histopathology) and in vivo (pharmacokinetic studies). Pharmacokinetic parameters, such as C(max), t(max), and AUC were estimated. The transdermal formulation in the present study was found to enhance the relative bioavailability of losartan potassium by 2.2 times with reference to an oral delivery. The increased bioavailability might be due to elimination of hepatic first pass metabolism. Thus, the transdermal formulation F3E with polymeric composition of Eudragit E 100 and polyvinyl pyrrolidone VA 64 (5:3) was found to provide prolonged steady state concentrations of losartan potassium with minimal fluctuations and improved bioavailability.
Losartan Potassium
Ex vivo
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