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Assessment of drug disposition in dermis: A microdialysis approach and its application in developing in-vitro in-vivo correlation (IVIVC) for topical dermatological drug products.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Assessment of drug disposition in dermis: A microdialysis approach and its application in developing in-vitro in-vivo correlation (IVIVC) for topical dermatological drug products./
作者:	Mehta, Jaydeep P.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2016,
面頁冊數:	138 p.
附註:	Source: Dissertation Abstracts International, Volume: 77-10(E), Section: B.
Contained By:	Dissertation Abstracts International77-10B(E).
標題:	Pharmaceutical sciences. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10127577
ISBN:	9781339856094

Assessment of drug disposition in dermis: A microdialysis approach and its application in developing in-vitro in-vivo correlation (IVIVC) for topical dermatological drug products.
Mehta, Jaydeep P.

Assessment of drug disposition in dermis: A microdialysis approach and its application in developing in-vitro in-vivo correlation (IVIVC) for topical dermatological drug products. - Ann Arbor : ProQuest Dissertations & Theses, 2016 - 138 p.

Source: Dissertation Abstracts International, Volume: 77-10(E), Section: B.

Thesis (Ph.D.)--Long Island University, The Brooklyn Center, 2016.

This item is not available from ProQuest Dissertations & Theses.

The skin is one of the most important and complex organ in our body. A better understanding of the skin morphology and transport pathways has led to immense development in the field of dermatological drug products. In spite of such advancement, one of the biggest challenge in developing topical dermatological drug products (TDDP) is the lack of a well-defined correlation between in-vitro permeation data and in-vivo dermal exposure data. For the approval of a generic TDDP, the current global regulations require clinical or pharmacodynamic evaluations for bioequivalence assessment. These clinical studies are often complex, expensive and statistically insensitive. Hence, there is a strong need to develop an in-vitro in-vivo correlation (IVIVC) technique for TDDP that could serve as a surrogate endpoint and speedup the drug development process.

ISBN: 9781339856094Subjects--Topical Terms:

3173021
Pharmaceutical sciences.

Assessment of drug disposition in dermis: A microdialysis approach and its application in developing in-vitro in-vivo correlation (IVIVC) for topical dermatological drug products.
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100 1 $a Mehta, Jaydeep P. $3 3345250
245 1 0 $a Assessment of drug disposition in dermis: A microdialysis approach and its application in developing in-vitro in-vivo correlation (IVIVC) for topical dermatological drug products.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2016
300 $a 138 p.
500 $a Source: Dissertation Abstracts International, Volume: 77-10(E), Section: B.
500 $a Adviser: Grazia Stagni.
502 $a Thesis (Ph.D.)--Long Island University, The Brooklyn Center, 2016.
506 $a This item is not available from ProQuest Dissertations & Theses.
520 $a The skin is one of the most important and complex organ in our body. A better understanding of the skin morphology and transport pathways has led to immense development in the field of dermatological drug products. In spite of such advancement, one of the biggest challenge in developing topical dermatological drug products (TDDP) is the lack of a well-defined correlation between in-vitro permeation data and in-vivo dermal exposure data. For the approval of a generic TDDP, the current global regulations require clinical or pharmacodynamic evaluations for bioequivalence assessment. These clinical studies are often complex, expensive and statistically insensitive. Hence, there is a strong need to develop an in-vitro in-vivo correlation (IVIVC) technique for TDDP that could serve as a surrogate endpoint and speedup the drug development process.
520 $a Most of the topical dermatological drug products intended for local therapeutic effect act directly in skin. In such cases, the plasma drug concentrations are insignificant and play a very limited role with respect to localized therapeutic effect in skin. Therefore, evaluation of plasma drug concentration is not an accurate measure for drug availability at site of action for topical drug products. For TDDP that act locally in dermis, assessing in-vivo dermal drug pharmacokinetics would be more relevant to optimize therapeutic outcome.
520 $a The concept of IVIVC is widely applied in the development of extended release oral dosage forms. In a typical Level A IVIVC approach, convolution of the in-vitro dissolution data with the disposition function (the unit impulse response, UIR) allows predicting plasma exposure. In such case, UIR can be determined from in-vivo IV bolus, immediate release tablet or oral solution data. Potentially, the same principles can be applied to the development of IVIVC for dermatological drug products. However, in case of TDDP, there are no method available to estimate UIR in skin.
520 $a The purpose of this study is to explore the possibility of estimating the drug disposition function in skin. Such dermal disposition function can then be combined with in-vitro permeation data to possibly predict in-vivo dermal exposure profile.
520 $a The dermal disposition studies involve technical challenges both at the drug delivery and sampling levels. A list of possible methods that can be used to investigate the dermal disposition include intradermal injection, microneedle, open-flow micro perfusion and dermal microdialysis. However, based on the limitations of each technique dermal microdialysis seems to be most suitable method to determine disposition of drug in dermis.
520 $a The main objective of this research was to explore the possibility of using dermal microdialysis as a potential tool to develop IVIVC for TDDP that act locally in dermis. Specifically, the project consists of two parts, (i) development of a novel method to estimate dermal disposition function (UIR) using microdialysis and (ii) validation of proposed approach, using estimated disposition function to predict the in-vivo dermal drug concentration from in-vitro permeation data following topical dermatological administration. The predicted dermal exposure data was compared to actual observed dermal data, obtained by performing in-vivo experiments using same topical formulations.
520 $a In the present study, Diphenhydramine hydrochloride (DPH), a classic antihistamine was used as a model drug because of its extensive topical use for various dermatological indications.
520 $a For the quantitative analysis of DPH, appropriate validation procedures were performed to confirm the reliability and reproducibility of the optimized reverse phase HPLC method. Preliminary in-vitro and in-vivo studies were performed to assess the feasibility of using microdialysis technique to estimate dermal disposition of DPH in rabbits. For in-vivo dermal disposition studies, three linear microdialysis probes were implanted in parallel into the shaved dorsal region of rabbit. The central probe was used for dermal DPH delivery and the two lateral probes were used for dermal DPH sampling. Disposition studies were performed in replicates at six different DPH dermal doses. The obtained dermal DPH concentrations versus time data were analyzed by Non-compartmental analysis (NCA) to assess the UIR. The observed dermal pharmacokinetic was indeed linear. The dermal Volume of distribution (Geo. mean range 111.12 to 231.18 ml) and Clearance (Geo. mean range 1.23 to 2.12 ml/min) estimates were consistent across different doses.
520 $a The in-vitro permeability and in-vivo dermal exposure experiments were performed to develop IVIVC using four different DPH gels, 2.0% Benadryl brand (Gel A), 2.0% CVS generic (Gel B), 3.5% (Gel C) and 5.0% (Gel D) (Gel A and B commercial formulations, Gel C and D compounded formulation). The characterization of all gels were performed by assessing product quality attributes such as content uniformity, viscosity, pH and physical appearance. The product performance was evaluated by in-vitro release tests (IVRT) and in-vitro permeation tests (IVPT) to assess the drug release from all the gels. The IVRT and IVPT were performed in vertical Franz cell assembly using synthetic cellulose and porcine ear skin membrane as diffusion barrier, respectively. Following topical application of all DPH gels, in-vivo dermal absorption studies were performed using microdialysis technique in rabbits.
520 $a For the Level A IVIVC, the numerical convolution approach was used to predict the point-to-point in-vivo dermal concentration of DPH from IVPT and UIR data, while the in-vivo absorption rate of DPH was estimated using model independent numerical deconvolution method. The in-vivo absorption data was graphically compared to in-vitro permeation data by Levy plot. For the Level C IVIVC, in-vitro flux and in-vivo Clearance estimates were used to predict in-vivo steady state dermal DPH concentration.
520 $a The results from the characterization tests were consistent across different gels. The estimated in-vitro steady state flux values (Mean +/- SD) for the gel A, B, C and D from IVRT studies were 521.40 +/- 93.81, 500.11 +/- 68.01, 1102.33 +/- 114.39 and 1684.67 +/- 178.66 microg/(cm2*hr) respectively. The observed in-vitro steady state flux estimates (Mean +/- SD) for gel A, B, C and D from IVPT were 183.73 +/- 9.87, 178.54 +/- 7.13, 236.68 +/- 9.06 and 342.00 +/- 32.92 microg/(cm2*hr) respectively. Similarly, the observed in-vivo flux estimates (Mean +/- SD) for gel A, B, C and D were 5.97 +/- 1.39, 5.21 +/- 1.05, 11.41 +/- 1.96 and 16.03 +/- 4.92 gg/(cm2*hr) respectively. The observed in-vivo flux on comparison with in-vitro flux at different concentration of DPH gel showed a linear correlation (R2 > 0.93). The results show that the simulated point-to-point and steady state dermal DPH concentrations following topical application, as estimated by Level A and Level C IVIVC approach were overestimated, as compared to actual observed DPH data. The observed differences between the actual and predicted data might be due to the differences of the skin membrane and so on in the in-vitro and in-vivo experimental conditions.
520 $a The findings from this study strongly suggest that in-vitro permeation test complemented with microdialysis based in-vivo dermal disposition studies can be developed as a potential useful tool to establish IVIVC for topical dermatological drug products.
590 $a School code: 0198.
650 4 $a Pharmaceutical sciences. $3 3173021
690 $a 0572
710 2 $a Long Island University, The Brooklyn Center. $3 1017735
773 0 $t Dissertation Abstracts International $g 77-10B(E).
790 $a 0198
791 $a Ph.D.
792 $a 2016
793 $a English
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