scholarly journals Inverse Mechanistic Modeling of Transdermal Drug Delivery for Fast Identification of Optimal Model Parameters

2021 ◽  
Vol 12 ◽  
Author(s):  
Thijs Defraeye ◽  
Flora Bahrami ◽  
René M. Rossi
Keyword(s):  
Drug Delivery ◽  
Inverse Modeling ◽  
Transdermal Drug Delivery ◽  
Drug Transport ◽  
Mechanistic Model ◽  
Mechanistic Modeling ◽  
Drug Uptake ◽  
Added Value ◽  
Model Parameters ◽  
Transdermal Drug Delivery Systems

Transdermal drug delivery systems are a key technology to administer drugs with a high first-pass effect in a non-invasive and controlled way. Physics-based modeling and simulation are on their way to become a cornerstone in the engineering of these healthcare devices since it provides a unique complementarity to experimental data and additional insights. Simulations enable to virtually probe the drug transport inside the skin at each point in time and space. However, the tedious experimental or numerical determination of material properties currently forms a bottleneck in the modeling workflow. We show that multiparameter inverse modeling to determine the drug diffusion and partition coefficients is a fast and reliable alternative. We demonstrate this strategy for transdermal delivery of fentanyl. We found that inverse modeling reduced the normalized root mean square deviation of the measured drug uptake flux from 26 to 9%, when compared to the experimental measurement of all skin properties. We found that this improved agreement with experiments was only possible if the diffusion in the reservoir holding the drug was smaller than the experimentally measured diffusion coefficients suggested. For indirect inverse modeling, which systematically explores the entire parametric space, 30,000 simulations were required. By relying on direct inverse modeling, we reduced the number of simulations to be performed to only 300, so a factor 100 difference. The modeling approach’s added value is that it can be calibrated once in-silico for all model parameters simultaneously by solely relying on a single measurement of the drug uptake flux evolution over time. We showed that this calibrated model could accurately be used to simulate transdermal patches with other drug doses. We showed that inverse modeling is a fast way to build up an accurate mechanistic model for drug delivery. This strategy opens the door to clinically ready therapy that is tailored to patients.

scholarly journals Inverse mechanistic modeling of transdermal drug delivery for fast identification of optimal model parameters

2020 ◽  
Author(s):  
Thijs Defraeye ◽  
Flora Bahrami ◽  
Rene M Rossi
Keyword(s):  
Drug Delivery ◽  
Inverse Modeling ◽  
Transdermal Drug Delivery ◽  
Drug Transport ◽  
Mechanistic Model ◽  
Mechanistic Modeling ◽  
Drug Uptake ◽  
Added Value ◽  
Model Parameters ◽  
Transdermal Drug Delivery Systems

Transdermal drug delivery systems are a key technology to administer drugs with a high first-pass effect in a non-invasive and controlled way. Physics-based modeling and simulation are on their way to become a cornerstone in the engineering of these healthcare devices since it provides a unique complementarity to experimental data and insights. Simulations enable to virtually probe the drug transport inside the skin at each point in time and space. However, the tedious experimental or numerical determination of material properties currently forms a bottleneck in the modeling workflow. We show that multiparameter inverse modeling to determine the drug diffusion and partition coefficients is a fast and reliable alternative. We demonstrate this strategy for transdermal delivery of fentanyl. We found that inverse modeling reduced the normalized root mean square deviation of the measured drug uptake flux from 26 to 9%, when compared to the experimental measurement of all skin properties. We found that this improved agreement with experiments was only possible if the diffusion in the reservoir holding the drug was smaller than the experimentally-measured diffusion coefficients suggested. For indirect inverse modeling, which systematically explores the entire parametric space, 30 000 simulations were required. By relying on direct inverse modeling, we reduced the number of simulations to be performed to only 300, so a factor 100 difference. The modeling approach's added value is that it can be calibrated once in-silico for all model parameters simultaneously by solely relying on a single measurement of the drug uptake flux evolution over time. We showed that this calibrated model could accurately be used to simulate transdermal patches with other drug doses. We showed that inverse modeling is a fast way to build up an accurate mechanistic model for drug delivery. This strategy opens the door to clinically-ready therapy that is tailored to patients.

scholarly journals Predicting transdermal fentanyl delivery using mechanistic simulations for tailored therapy

2020 ◽  
Author(s):  
Thijs Defraeye ◽  
Flora Bahrami ◽  
Lu Ding ◽  
Riccardo Innocenti Malini ◽  
Alexandre Terrier ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Drug Release ◽  
In Silico ◽  
Transdermal Drug Delivery ◽  
Drug Delivery Systems ◽  
Delivery Systems ◽  
Drug Uptake ◽  
Transdermal Fentanyl ◽  
Transdermal Drug Delivery Systems ◽  
Drug Flux

Transdermal drug delivery is a key technology for administering drugs. However, most devices are “one-size-fits-all”, even though drug diffusion through the skin varies significantly from person-to-person. For next-generation devices, personalization for optimal drug release would benefit from an augmented insight into the drug release and percutaneous uptake kinetics. Our objective was to quantify the changes in transdermal fentanyl uptake with regards to the patient’s age and the anatomical location where the patch was placed. We also explored to which extent the drug flux from the patch could be altered by miniaturizing the contact surface area of the patch reservoir with the skin. To this end, we used validated mechanistic modeling of fentanyl diffusion, storage, and partitioning in the epidermis to quantify drug release from the patch and the uptake within the skin. A superior spatiotemporal resolution compared to experimental methods enabled in-silico identification of peak concentrations and fluxes, and the amount of stored drug and bioavailability. The patients’ drug uptake showed a 36% difference between different anatomical locations after 72 h, but there was a strong interpatient variability. With aging, the drug uptake from the transdermal patch became slower and less potent. A 70-year-old patient received 26% less drug over the 72-h application period, compared to an 18-year-old patient. Additionally, a novel concept of using micron-sized drug reservoirs was explored in silico. These reservoirs induced a much higher local flux (µg cm-2 h-1) than conventional patches. Up to a 200-fold increase in the drug flux was obtained from these small reservoirs. This effect was mainly caused by transverse diffusion in the stratum corneum, which is not relevant for much larger conventional patches. These micron-sized drug reservoirs open new ways to individualize reservoir design and thus transdermal therapy. Such computer-aided engineering tools also have great potential for in-silico design and precise control of drug delivery systems. Here, the validated mechanistic models can serve as a key building block for developing digital twins for transdermal drug delivery systems.

Transdermal Drug Delivery Systems and their Potential in Alzheimer’s Disease Management

2020 ◽  
Vol 19 (5) ◽  
pp. 360-373 ◽  
Author(s):  
Panoraia I. Siafaka ◽  
Ece Ö. Bülbül ◽  
Gökce Mutlu ◽  
Mehmet E. Okur ◽  
Ioannis D. Karantas ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Drug Delivery ◽  
Alzheimer's Disease ◽  
Disease Management ◽  
Transdermal Drug Delivery ◽  
Drug Delivery Systems ◽  
Delivery Systems ◽  
Oral Dosage ◽  
Transdermal Administration ◽  
Transdermal Drug Delivery Systems

Alzheimer's disease is a neuropathological disease with symptoms such as language problems, confusion as to place or time, loss of interest in activities, which were previously enjoyed, behavioral changes, and memory loss. Alzheimer's disease and other types of dementia affect almost 46.8 million people globally and are estimated to strike about 131.5 million people in 2050. It has been reported that Alzheimer's is the sixth main cause of mortality. The most used drugs, which are currently approved by the Food, and Drug Administration for Alzheimer’s disease are donepezil, rivastigmine, galantamine, memantine, and the combination of donepezil and memantine. However, most of the drugs present various adverse effects. Recently, the transdermal drug delivery route has gained increasing attention as an emerging tool for Alzheimer's disease management. Besides, transdermal drug delivery systems seem to provide hope for the management of various diseases, due to the advantages that they offer in comparison with oral dosage forms. Herein, the current advancements in transdermal studies with potent features to achieve better Alzheimer's disease management are presented. Many researchers have shown that the transdermal systems provide higher efficiency since the first-pass hepatic metabolism effect can be avoided and a prolonged drug release rate can be achieved. In summary, the transdermal administration of Alzheimer's drugs is an interesting and promising topic, which should be further elaborated and studied.

Functionally Tailored Electro-Sensitive Poly(Acrylamide)-g-Pectin Copolymer Hydrogel for Transdermal Drug Delivery Application: Synthesis, Characterization, In-vitro and Ex-vivo Evaluation

2020 ◽  
Vol 10 (3) ◽  
pp. 185-196
Author(s):  
Sudha B. Patil ◽  
Syed Z. Inamdar ◽  
Kakarla R. Reddy ◽  
Anjanapura V. Raghu ◽  
Krishnamachari G. Akamanchi ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Drug Release ◽  
Transdermal Drug Delivery ◽  
Ex Vivo ◽  
Transmission Rate ◽  
Electric Signal ◽  
Poly Vinyl Alcohol ◽  
Electric Stimulus ◽  
Copolymer Hydrogel ◽  
Transdermal Drug Delivery Systems

Background and Objectives: To develop electro-sensitive transdermal drug delivery systems (ETDDS) using polyacrylamide-grafted-pectin (PAAm-g-PCT) copolymer hydrogel for rivastigmine delivery. Methods: Free radical polymerization and alkaline hydrolysis technique was employed to synthesize PAAm-g-PCT copolymer hydrogel. The PAAm-g-PCT copolymeric hydrogel was used as a reservoir and cross-linked blend films of PCT and poly(vinyl alcohol) as rate-controlling membranes (RCMs) to prepare ETDDS. Results: The pH of the hydrogel reservoir was found to be in the range of 6.81 to 6.93 and drug content was 89.05 to 96.29%. The thickness of RCMs was in the range of 51 to 99 μ and RCMs showed permeability behavior against water vapors. There was a reduction in the water vapor transmission rate as the glutaraldehyde (GA) concentration was increased. The drug permeation rate from the ETDDS was enhanced under the influence of electric stimulus against the absence of an electric stimulus. The increase in flux by 1.5 fold was recorded with applied electric stimulus. The reduction in drug permeability observed when the concentration of GA was increased. Whereas, the permeability of the drug was augmented as an electric current was changed from 2 to 8 mA. The pulsatile drug release under “on– off” cycle of electric stimulus witnessed a faster drug release under ‘on’ condition and it was slow under ‘off’ condition. The alteration in skin composition after electrical stimulation was confirmed through histopathology studies. Conclusion: The PAAm-g-PCT copolymer hydrogel is a useful carrier for transdermal drug delivery activated by an electric signal to provide on-demand release of rivastigmine.

Electrically Triggered Transdermal Drug Delivery Utilizing Poly(Acrylamide)-graft-Guar Gum: Synthesis, Characterization and Formulation Development

2019 ◽  
Vol 3 (1) ◽  
pp. 64-74 ◽  
Author(s):  
Ravindra P. Birajdar ◽  
Sudha S. Patil ◽  
Vijaykumar V. Alange ◽  
Raghavendra V. Kulkarni
Keyword(s):  
Drug Delivery ◽  
Electric Current ◽  
Transdermal Drug Delivery ◽  
Guar Gum ◽  
Fold Increase ◽  
Formulation Development ◽  
Neutralization Equivalent ◽  
Electric Stimulus ◽  
Drug Permeation ◽  
Transdermal Drug Delivery Systems

Objective: The study aimed to prepare electrically-triggered transdermal drug delivery systems (ETDS) using electrically responsive polyacrylamide-graft-gaur gum (PAAm-g-GaG) copolymer. Methods: The PAAm-g-GaG copolymer was synthesized by adopting free radical polymerization grafting method. This PAAm-g-GaG copolymer hydrogel acts as a drug reservoir and blend films of Guar Gum (GaG) and Polyvinyl Alcohol (PVA) were included as Rate Controlling Membranes (RCM) in the system. The PAAm-g-GaG copolymer was characterized by FTIR, neutralization equivalent values, thermogravimetric analysis and elemental analysis. Results: On the basis of results obtained, it is implicit that the drug permeation decreased with an increase in the concentration of glutaraldehyde and RCM thickness; while drug permeation rate was increased with increasing applied electric current strength from 2 to 8 mA. A two fold increase in flux values was observed with the application of DC electric current. An increase in drug permeation was witnessed under on condition of electric stimulus and permeation was decreased when electric stimulus was "off". The skin histopathology study confirmed the changes in skin structure when electrical stimulus was applied. Conclusion: The electrically-sensitive PAAm-g-GaG copolymer is a useful biomaterial for transdermal drug delivery application.

scholarly journals Enhancement strategies for transdermal drug delivery systems: current trends and applications

2021 ◽  
Author(s):  
Delly Ramadon ◽  
Maeliosa T. C. McCrudden ◽  
Aaron J. Courtenay ◽  
Ryan F. Donnelly
Keyword(s):  
Drug Delivery ◽  
Stratum Corneum ◽  
Transdermal Delivery ◽  
Transdermal Drug Delivery ◽  
Drug Delivery Systems ◽  
Delivery Systems ◽  
Global Market ◽  
Therapeutic Drug ◽  
Current Trends ◽  
Transdermal Drug Delivery Systems

AbstractTransdermal drug delivery systems have become an intriguing research topic in pharmaceutical technology area and one of the most frequently developed pharmaceutical products in global market. The use of these systems can overcome associated drawbacks of other delivery routes, such as oral and parenteral. The authors will review current trends, and future applications of transdermal technologies, with specific focus on providing a comprehensive understanding of transdermal drug delivery systems and enhancement strategies. This article will initially discuss each transdermal enhancement method used in the development of first-generation transdermal products. These methods include drug/vehicle interactions, vesicles and particles, stratum corneum modification, energy-driven methods and stratum corneum bypassing techniques. Through suitable design and implementation of active stratum corneum bypassing methods, notably microneedle technology, transdermal delivery systems have been shown to deliver both low and high molecular weight drugs. Microneedle technology platforms have proven themselves to be more versatile than other transdermal systems with opportunities for intradermal delivery of drugs/biotherapeutics and therapeutic drug monitoring. These have shown that microneedles have been a prospective strategy for improving transdermal delivery systems. Graphical abstract

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