Drug In Adhesive Patch Research Articles

Enhanced Skin Permeation of 5-Fluorouracil through Drug-in-Adhesive Topical Patches.

5-fluorouracil (5-FU), commercially available as a topical product, is approved for non-melanoma skin cancer (NMSC) treatment with several clinical limitations. This work aimed to develop 5-FU-loaded topical patches as a potential alternative to overcome such drawbacks. The patches offer accurate dosing, controlled drug release and improved patient compliance. Our study highlights the development of Eudragit® E (EuE)-based drug-in-adhesive (DIA) patches containing a clinically significant high level of 5-FU (approximately 450 µg/cm2) formulated with various chemical permeation enhancers. The patches containing Transcutol® (Patch-TRAN) or oleic acid (Patch-OA) demonstrated significantly higher skin penetration ex vivo than their control counterpart, reaching 5-FU concentrations of 76.39 ± 27.7 µg/cm2 and 82.56 ± 8.2 µg/cm2, respectively. Furthermore, the findings from in vitro permeation studies also validated the superior skin permeation of 5-FU achieved by Patch-OA and Patch-TRAN over 72 h. Moreover, the EuE-based DIA patch platform demonstrated suitable adhesive and mechanical properties with an excellent safety profile evaluated through an inaugural in vivo human study involving 11 healthy volunteers. In conclusion, the DIA patches could be a novel alternative option for NMSC as the patches effectively deliver 5-FU into the dermis layer and receptor compartment ex vivo for an extended period with excellent mechanical and safety profiles.

Investigating the influences of intermolecular interactions on viscoelastic performance of pressure-sensitive adhesive by FT–IR spectroscopy and molecular modeling

Objective: This study was to clarify the molecular mechanism of viscoelastic performance variations of pressure-sensitive adhesive (PSA) with the addition of drugs by FT-IR spectroscopy and molecular modeling.Significance: Viscoelastic performance of PSA was frequently changed by the addition of drugs in drug-in-adhesive (DIA) patches. It may cause decrease of the physical stability and drug bio-adhesion issues for the development of DIA patch. But, the molecular details of drug–PSA interaction are not clarified.Methods: Model drugs including propranolol (PRO), oxybutynin (OXY), and escitalopram were added into patch with hydroxyl PSA (10%, w/w). Rheological study and thermal analysis were used to characterize the viscoelastic performance and free volume of PSA, respectively. 1H NMR was used to determine the quantity of hydroxyl group in the PSA. FT-IR study and molecular modeling were conducted to describe the types and interaction sites between drug and PSA molecule.Results: The results demonstrated that PRO interacted with –OH and –COOR groups of PSA, which interrupted the interaction between the PSA molecules, resulting in a plasticizing phenomenon of PSA. Escitalopram mainly interacted with –OH of PSA and decreased the rigidity of the drug-loaded PSA only in the high-frequency region. No obvious interaction was found between OXY and PSA, and the viscoelastic performance of PSA did not change significantly.Conclusion: The present study described the molecular mechanism of viscoelastic performance variation, especially the plasticizing effect. These results were essential for the design and development of transdermal patches from the viewpoint of viscoelastic performance.

Development of Tizanidine Drug-in-Adhesive Patch: Molecular Mechanism of Permeation Enhancer on Regulating Miscibility and Drug Release by Affecting the Status of Ion-Pair in Polymer Matrix

The objective of this work was to develop a drug-in-adhesive (DIA) patch of TIZ by employing ion-pair and permeation enhancer to increase drug-polymer miscibility and drug release. Special attention was paid on the regulation effect of permeation enhancer on ion-pair status in pressure sensitive adhesives (PSA). Formulation factors including TIZ-fatty acids ion-pair, drug loading and permeation enhancer were investigated by ex-vivo transdermal experiments. Optimized patch was evaluated by pharmacokinetics study. The better polarity similarity and strong hydrogen bonding interactions between TIZ-caproic acid ion-pair (TIZ-C6) and PSA was confirmed by polarity determination, FT-IR, TOPEM of MDSC and theoretical calculation, which determined enhanced miscibility of ion-pair and PSA. The permeation enhancer affected status of ion-pair in PSA by regulating polarity similarity and interaction between ion-pair and PSA, resulting in increased drug-PSA miscibility and drug release, which was characterized by FT-IR, polarity determination, thermal analysis and molecular dynamics simulation. The optimized patch showed high drug-polymer miscibility and drug skin permeability with AUC0-t of 14641.12 ± 854.45 h ng/mL and Cmax of 834.55 ± 155.68 ng/mL, which was significantly higher than the control group. In conclusion, DIA patch of TIZ was prepared and it supplied a reference for design of DIA patches with TIZ.

SEBS block copolymers as novel materials to design transdermal patches.

Styrene-block-(ethylene-co-butylene)-block-styrene (SEBS) copolymers are biocompatible elastomers with outstanding stability to UV radiation. This work addresses the potentialities of this class of elastomers for the development of transdermal patches. The influence of SEBS molecular weight, plasticizer and tackifier type on rheological pattern, debonding mechanisms, adhesive properties (i.e., tack, shear and peel adhesion) as well as on the in vitro biopharmaceutical performances (i.e., drug release and skin permeability) was investigated using ibuprofen as model drug. The relationships between the linear and non-linear rheological properties and the main adhesive and biopharmaceutical properties of the prepared patches have been demonstrated. The higher the viscous component of the matrix, the lower its cohesiveness and the faster the drug release rate. The in vitro skin permeability of ibuprofen was not limited by the polymeric matrix, even if compared to the commercial reference product. In conclusion, SEBS copolymers are suitable materials to design drug in-adhesive patches. In particular, SEBS-low molecular weight is the polymer worthy of consideration because of its favorable viscoelastic behavior.

Drug in Adhesive Transdermal Formulation of Valsartan and Nifedipine: Pharmacokinetics and Pharmacodynamics in Rats

Background: The increasing complications associated with hypertension often require a combination of two or more drugs acting through different routes to counter the elevated blood pressure. Objective: The present investigation envisaged at preparing and evaluating a transdermal formulation containing gelled microemulsion drug in adhesive (DIA) patch for simultaneous systemic delivery of valsartan and nifedipine aimed at effective management of hypertension. Methods: An optimized microemulsion was prepared by using Captex® 500 (7.34% w/w), Capmul® MCM (4.24% w/w), Acrysol EL 135 (24.43% w/w), Transcutol P® (5% w/w) and water (58.9% w/w). Gelling was contributed by polyvinylpyrrolidone K 90F and polyethyleneimine where the latter also conferred skin adhesion properties to the patch. DIA patches were evaluated for in vitro drug release as well as in vivo pharmacokinetics and pharmacodynamics in rats. Results: In vitro permeation of nifedipine or valsartan from the selected DIA patch was 10.67-fold and 1.25-fold higher as compared to their aqueous dispersions. The relative bioavailability of nifedipine was 1.34 and that of valsartan was 2.18 from this DIA patch with respect to the oral administration of their aqueous suspension. Conclusion: Transdermal delivery of either drug alone was not effective in reducing methyl prednisolone acetate-induced hypertension, whereas, simultaneous transdermal delivery of both drugs from DIA patch effectively maintained systolic blood pressure at a normal level in these rats for 20 h.

Effect of permeation enhancers on in vitro release and transdermal delivery of lamotrigine from Eudragit\xaeRS100 polymer matrix-type drug in adhesive patches

The drug-in-adhesive (DIA)-type matrix patches of lamotrigine are developed using variable permeation enhancers (oleic acid, PG, lemon oil and aloe vera), and drug in vitro release and its permeation are evaluated. Lamotrigine has been long used as an anti-epileptic, mood stabilizer, to treat bipolar disorder in adults and off label as an antidepressant. lamotrigine matrix patches comprising of Eudragit®RS100 (rate-controlling polymer) and DuroTak® 387-2510 (adhesive) were prepared by pouring the solution on backing membrane (3M-9720). The thickness of 120 µm was adjusted through micrometer film applicator. USP Apparatus V was used for the evaluation of release profile, which was fitted into various mathematical models. Quality characteristics of patches were determined through weight variation, moisture content, moisture uptake and drug content evaluation. FTIR studies were performed for drug-excipient compatibility; Franz diffusion cell was employed for studying in vitro permeation parameters such as flux, lag time, and ER. Skin sensitivity study of optimized patch was also performed. The release from patches comprising of PG and oleic acid was maximum, i.e., 96.24 ± 1.15% and 91.12 ± 1.11%, respectively. Formulations (A1–A5) exhibited Makoid–Banakar release profile. Formulation A3 consisting of oleic acid was optimized due to enhanced permeation of drug across skin compared to other enhancers with enhancement ratio of 3.55. Skin sensitivity study revealed patch as safe and non-allergenic. The study demonstrates that oleic acid can be used as a suitable permeation enhancer for transdermal delivery of lamotrigine from matrix-type patches.

Development of Drug-in-Adhesive Patch with a Honeycomb Film as a Backing Layer.

Excess stripping of stratum corneum (SC) layers by patch-peeling from the skin surface is one cause of skin irritation. High SC hydration by patch occlusion may also cause skin irritation, although the occlusive technique is preferable to increase the skin permeation of topically applied drugs. In the present study, film having a honeycomb structure was selected as the backing layer of a drug-in-adhesive (DIA) patch to reduce peeling of the SC without losing adhesion force to the skin surface, as well as decreasing the skin permeation of a model drug, tulobuterol. The usefulness of the DIA patch with honeycomb film was evaluated by transepidermal water loss (TEWL) changes, amount of SC removed by patch-peeling, distribution pattern of removed SC on the adhesive layer, and water permeation through the patch. Furthermore, skin permeation and release profiles of tulobuterol from the DIA patch were investigated. Significantly (p<0.05) less TEWL change was observed after removal of the patch with a honeycomb film compared with the conventional pressure-sensitive adhesive patch, and no difference in tulobuterol permeation through skin from the patches was confirmed regardless of the type of backing layer. In addition, a lower amount of SC was removed by the peeling of the patch with a honeycomb film. The results suggest that DIA patches with a honeycomb film as a backing layer may be used to achieve less SC removal without reducing the skin permeation of drugs.

In Depth Analysis of Pressure-Sensitive Adhesive Patch-Assisted Delivery of Memantine and Donepezil Using Physiologically Based Pharmacokinetic Modeling and in Vitro/in Vivo Correlations.

The objective of this work was to evaluate the feasibility of transdermal delivery of two widely prescribed dementia drugs for the Alzheimer's disease. In this regard, the drug in adhesive patches of memantine (ME) co-loaded with donepezil (DO) was prepared using an ethylene vinyl acetate polymer and characterized for drug content, the crystallinity of drugs in the polymer matrix, and in vitro permeation. To understand the different physical and chemical processes underlying the percutaneous absorption, it is required to employ a comprehensive model that accounts for the anatomy and physiology of the skin. A transdermal physiologically based pharmacokinetic (TPBPK) model was developed and was integrated in a compartmental pharmacokinetic model to predict the plasma drug concentrations in rats. The model predictions showed a good fit with the experimental data, as evaluated by the prediction error calculated for both drugs. It was evident from the simulations that the drug diffusivity and partition coefficient in the polymer matrix are the critical parameters that affect the drug release from the vehicle and subsequently influence the in vivo pharmacokinetic profile. Moreover, a correlation function was built between the in vitro permeation data and in vivo absorption for both ME and DO. A good point-to-point in vitro/in vivo correlation (IVIVC, Level A correlation) was achieved by predicting the plasma concentrations with convolution for the entire study duration. The results of our study suggested that the implementation of mechanistic modeling along with IVIVC can be a valuable tool to evaluate the relative effects of formulation variables on the bioavailability from transdermal delivery systems.

In vitro permeation and stability studies on developed drug-in-adhesive transdermal patch of simvastatin

The transdermal drug-in-adhesive (DIA) patch of simvastatin (SM) was developed using acrylic adhesives such as DURO-TAK® 87-9301, DURO-TAK® 87-4287, DURO-TAK® 87-235A. The patches were evaluated for in vitro drug permeation across the pork ear skin using diffusion cell and stability studies. Among the three acrylic adhesives used, DURO-TAK® 87-9301 exhibited maximum flux (5.18 ± 0.23 µg/cm2/h). To further enhance the drug permeation, isopropyl myristate (IPM), d-limonene and 1,8-cineol as penetration enhancers (PEs) were incorporated into the DIA patch prepared from DURO-TAK® 87-9301. Out of those, IPM containing patch exhibited a flux of 16.45 ± 1.67 µg/cm2/h revealing that IPM is the best PE. The stability study was carried out on optimized fresh (SA4) and 6 months old patches stored at room and at accelerated condition (40 ± 2 °C/75 ± 5%RH) using FTIR, DSC and SEM techniques. Significant shift of peaks were not observed in FTIR spectra and DSC thermograms of the patches after the stability period. SEM micrographs of patches did not show any evidence of recrystallization indicating the presence of drug in the molecular form throughout the adhesive matrix. The investigation reveals that the DIA patch studied as above is stable and may serve as a potential drug delivery system for simvastatin.

Drug in adhesive patch of palonosetron: Effect of pressure sensitive adhesive on drug skin permeation and in vitro-in vivo correlation

Palonosetron (PAL) is recommended for the prevention of chemotherapy-induced nausea and vomiting. The aim of this study was to develop a long-acting PAL transdermal patch to improve patient compliance. We were particularly concerned about the effect of pressure sensitive adhesives (PSAs) on PAL skin permeability. Formulation factors including PSAs, backing films and drug loadings were investigated in the in vitro skin permeation study using rabbit skin. Fourier transform infrared spectrometer study and thermal analysis were conducted to investigate the drug-PSA interaction and thermodynamic activity of PSAs, respectively. The results indicated that high drug skin permeation amount was obtained in PSA DURO-TAK®87-2516, which had low interaction potential with PAL and high thermodynamic activity. The optimized patch was composed of PAL of 8 %, DURO-TAK®87-2516 as PSA, CoTran™ 9700 as backing film and Scotchpak™ 9744 as release liner. The in vitro skin permeation amount of the optimized patch was 734.0±55.8μg/cm2 during 3-day administration. The absolute bioavailability of the optimized patch was 43 % in rabbit and a good in vitro-in vivo correlation coefficient was obtained (R2=0.989). These results indicated the feasibility of PAL transdermal patch in the prevention of chemotherapy-induced nausea and vomiting.

Transdermal patches for D-threo-methylphenidate (free base): Formulation aspects and in vivo pharmacokinetics

This study was designed to develop a drug-in-adhesive (DIA) type transdermal drug delivery system (TDDS) for D-threo-methylphenidate (D-threo-MP) that could be further developed for treating Attention-Deficit/Hyperactivity Disorder (ADHD) in children. During initial formulation optimization, three formulation factors, i.e., different adhesives, permeation enhancers and drug loading of D-threo-MP were screened using vertical Franz diffusion cells across newborn pig skin. A patch containing 15% (w/w) D-threo-MP in DURO-TAK®87-4098 was considered as an optimum patch which was selected for in vivo studies. The optimum D-threo-MP patch pharmacokinetic parameters were determined in Sprague Dawley (SD) rats and bama miniature pigs (Sus scrofa domestica) after application of transdermal patches, intravenous (i.v.) injection or oral administration. The absolute bioavailability and the relative bioavailability of D-threo-MP DIA patch in the SD rats model were 53.4% and 218.8%, respectively, and the relative bioavailability was 83.4% in the bama miniature pigs model. In this study, we showed that the optimized D-threo-MP patches could be further developed for treating Attention-Deficit/Hyperactivity Disorder (ADHD) in children.

Development of drug-in-adhesive patch formulations for transdermal delivery of fluoxetine: In vitro and in vivo evaluations

The aim of this study was to develop drug-in adhesive (DIA) patch formulations for the transdermal delivery of fluoxetine (FX). The DIA patch formulations containing FX were prepared and optimized with various pressure sensitive adhesives, drug contents and enhancers. Among the various formulations, DuroTak 87-502B-based patch formulation containing 20% (w/w) FX with no enhancer was selected for in vivo pharmacokinetic study based on in vitro permeation studies using hairless mouse, rat and human cadaver skins. The Cmax of FX after the transdermal administration of the optimized patch formulation in rats was 52.38ng/ml, and plasma concentration of FX was maintained for 36h. Moreover, the predicted human Css (55.79ng/ml) and Cmax (27.35ng/ml) were in good agreement with the reported plasma levels (15–55ng/ml) of oral FX in clinical applications. These results suggest that the optimized patch formulation could be further developed for clinical applications, providing the therapeutic plasma level of FX over an extended period. To the best of our knowledge, our results are the first reported in vitro and in vivo data on the preparation and optimization of FX-loaded DIA patch, showing its feasibility as an effective transdermal delivery system for FX.

Drug in Adhesive Patch of Zolmitriptan: Formulation and In vitro /In vivo Correlation.

The objective of the present study was to develop transdermal patch for zolmitriptan, determine its in vivo absorption using the rabbit skin. Solvent evaporation technique prepared zolmitriptan patch was settled in two-chamber diffusion cell combined with excised rabbit abdomen skin for permeation study. A sufficient cumulative penetration amount of zolmitriptan (258.5 ± 26.9 μg/cm(2) in 24 h) was achieved by the formulation of 4% zolmitriptan, 10% Azone, and adhesive of DURO-TAK® 87-4098. Pharmacokinetic parameters were determined via i.v. and transdermal administrations using animal model of rabbit. The results revealed that the absolute bioavailability was about 63%. Zolmitriptan could be detected with drug level of 88 ± 51 ng/mL after transdermal administration of 15 min. The in vivo absorption curve obtained by deconvolution approach using WinNonlin® program was correlated well with the in vitro permeation curve, the correlation coefficient R is 0.84, and the result indicated that in vitro skin permeation experiments were useful to predict the in vivo performance. In addition, little skin irritation was found in the irritation study. As a conclusion, the optimized zolmitriptan transdermal patches could effectively deliver adequate drug into systemic circulation in short time without producing any irritation phenomenon and worth to be developed.

Formulation and biopharmaceutical evaluation of a transdermal patch containing aceclofenac

To reduce the adverse effects of aceclofenac that accompanied with oral administration of this drug, transdermal patches in the form of drug-in-adhesive (DIA) patches, containing aceclofenac, were formulated. The effect of formulation factors on the skin permeation of the drug and physical properties of the patch were evaluated using excised rat skins. The optimized patch contained 12 % aceclofenac and 20 % lauryl alcohol in DT-2852 as a pressure-sensitive adhesive. The pharmacokinetic characteristics of the DIA patch were determined after application of the transdermal patches to human volunteers. The calculated relative bioavailability of the aceclofenac DIA patch was 18.2 % compared to oral administration of the drug. The findings of this study suggest that transdermal application of aceclofenac can substitute for oral administration of the drug.

Development and evaluation of a monolithic drug-in-adhesive patch for valsartan

The purpose of this study was to investigate the feasibility of a monolithic drug-in-adhesive (DIA) patch as a transdermal therapeutic system for the administration of valsartan (VAL). To improve the penetration of VAL in the patch, several chemical penetration enhancers were investigated by in vitro hairless mouse and Yucatan micro pig (YMP) skin permeation studies. A combination of isopropyl myristate (IPM)/diisooctyl sodium sulfosuccinate (AOT) most strongly enhanced the permeation of VAL. Since the concentration of VAL through the patch in hairless rat (HR) in vivo was correlated with that in HR skin in vitro, VAL that permeated through the skin could effectively pass into the systemic circulation. The plasma concentration–time profile of VAL after the patch was applied in humans was estimated by a convolution technique from the results of the in vitro YMP study, which indicated that the concentration of VAL could be sufficient to produce a pharmacological effect. These results demonstrate that the combination of IPM/AOT may be useful for the development of a practical DIA patch for VAL.

Formulation and biopharmaceutical evaluation of a transdermal patch containing letrozole

The purpose of this study was to formulate a drug-in-adhesive (DIA) transdermal patch containing letrozole, a third generation aromatase inhibitor for the treatment of breast cancer, using pressure-sensitive-adhesives (PSAs) and to evaluate the percutaneous penetration and pharmacokinetics of letrozole after transdermal administration, compared with that for the oral route. The formulation factors for such a patch, including the PSAs, enhancers and amount of drug loaded were investigated. Among the tested preparations, the formulation with DURO-TAK 87-4098, Azone and propylene glycol showed the highest letrozole permeation. The pharmacokinetic characteristics of an optimized DIA patch containing letrozole were determined using rats, while orally administered letrozole in solution was used as a control. The pharmacokinetic parameter, such as the mean residence time (MRT) was significantly (p<0.05) different following transdermal administration compared with oral administration. The in vivo results observed with the patches in rats were in good agreement with the plasma concentrations predicted from the in vitro penetration data. As a patient-friendly, convenient, high local drug concentration and sustained dosing therapeutic system, the transdermal patches incorporating letrozole provide a useful strategy for the prevention and treatment of breast cancer.

Preparation and In Vitro Evaluation of a New Fentanyl Patch Based on Acrylic/Silicone Pressure-Sensitive Adhesive Blends

In this study, the influence of the ratio of silicone (Si) to acrylic pressure-sensitive adhesive (PSA), polyvinyl pyrrolidone (PVP), and lauryl alcohol (LA) % (wt/wt) on the properties of a drug in adhesive patch containing 4% (wt/wt) fentanyl as model drug was evaluated. The dependent variables selected were drug solubility, in vitro drug release in the platforms as well as adhesion properties including peel strength and tack value. By using the central composite design of Design Expert software, it was found that the effect of each factor was different, yet all had influenced dependent variables significantly (p < .05). Quadratic model generated for various response variables using backward regression analysis was found to be statistically significant (p < .05). It was deduced that the presence of PVP and Si displayed similar trends on drug solubility and release. Each role played by Si with LA and PVP in release rate was separately investigated, and it was found that the presence of PVP and LA in lowering the amount of drug released was more dominant compared with that of Si. The release patterns at the early and later stages follow the Higuchi and semiempirical models, respectively. Effect of PVP as well as Si and LA were similar on tack value. The influence of LA compared to peeling characteristics of Si system was more pronounced.

Formulation and biopharmaceutical evaluation of transdermal patch containing benztropine

Benztropine (BZ) is a potent muscarinic receptor antagonist that has been used for the treatment of Parkinson disease. However, the oral administration of BZ is often limited because of its many dose-related side effects. In this study, BZ was formulated into drug-in adhesive (DIA) patches in an attempt to overcome these problems. The effects of the formulation factors including pressure-sensitive adhesive (PSA), enhancer, the loading amount of the drug and patch thickness on the skin permeation of the drug were evaluated using excised rat skin. The optimized patch contained 10% BZ in Duro-Tak ® 2525 as a PSA at a thickness of 100 μm. The pharmacokinetic characteristics of the optimized DIA patch were determined after the transdermal application to rabbits. The calculated relative bioavailability of BZ in the DIA patch was 54% compared to the oral administration of BZ mesylate. This suggests that the transdermal application of BZ in a DIA patch may be used for the treatment of Parkinson disease.