Intranasal Drug Delivery of Frovatriptan Succinate–Loaded Polymeric Nanoparticles for Brain Targeting

The objective of the present study was to develop polymeric nanoparticles (PNPs) of frovatriptan succinate for brain targeting by nasal route. Double emulsion method was used to increase the entrapment efficiency of hydrophilic drug, and formulation was optimized by central composite design to achieve critical quality attributes namely particle size, zeta potential, and entrapment efficiency. Optimized batch was evaluated for surface morphology, in vitro release, permeation across nasal mucosa, stability, histopathology, and brain tissue uptake study. Prepared PNPs were found to be smooth with particle size of 264.4 ± 0.04 nm, zeta potential ?35.17 ± 0.07 mV, and 65.2 ± 0.06% entrapment efficiency. PNPs showed biphasic release pattern, initial burst release followed by sustained release up to 72 h. Ex vivo diffusion study using goat nasal mucosa at pH 6.8 revealed that PNPs permeation across nasal mucosa was about 3 times more than the pure drug solution, and quick delivery of PNPs in brain region was confirmed by fluorescence microscopic evaluation in male Wistar rats after intranasal administration. Histopathology studies further revealed integrity of nasal mucosa after treatment with PNPs. The investigation indicated that hydrophilic drug, frovatriptan succinate can be successfully entrapped in PNPs to target brain via nasal delivery, and thus it could be an effective approach for nose to brain delivery.     

Arginine-α, β-dehydrophenylalanine Dipeptide Nanoparticles for pH-Responsive Drug Delivery

Purpose

Nanoparticles (NPs) exhibiting responsiveness towards pH variations in organs, tissue microenvironments and cellular compartments can significantly add on to the drug delivery potential. Here, we have developed NPs from an amphipathic dipeptide, Arginine-α, β-dehydrophenylalanine (RΔF), and tried to explore their pH responsive drug delivery potential in various cancer cells.

Methods

RΔF-NPs were architectured by harnessing the process of molecular self-assembly followed by the assessment of effect of pH on NPs morphology using zetasizer, SEM and CD. FTIR and PXRD analysis of the dipeptide and doxorubicin (Dox) were carried out for compatibility assessment followed by encapsulation of Dox in RΔF-NPs. RΔF-Dox-NPs were evaluated for pH dependent release as well as for in-vitro cellular internalization and efficacy in cancer cells.

Results

RΔF self-assembled to form monodispersed particles at pH 7. SEM analysis revealed a loss of overall particle morphology along with particle aggregation at highly acidic and basic pH respectively. The NPs demonstrated a slow and sustained release behaviour at pH 7 (97.64?±?4.71% after 36 h) in comparison to pH 2 (90.27?±?1.45% after 8 h) and pH 10 (96.39?±?3.87% after 12 h). In-vitro efficacy studies carried-out in various cancer cells revealed that RΔF-Dox-NPs exhibited higher efficacy with 1.65, 1.95 and 13.34 fold lower IC₅₀ values in comparison to Dox in C6, HCT-116 and AGS cell lines.

Conclusions

RΔF-Dox-NPs with higher drug release at acidic pH, enhanced internalization in cancer cells along with higher cytotoxic potential can act as effective pH responsive drug delivery systems.

     

Preparation and Characterization of Insulin–Surfactant Complexes for Loading into Lipid-Based Drug Delivery Systems

Insulin suffers from poor oral bioavailability, but lipid-based drug delivery systems (DDS) may constitute promising tools for improving this. Loading of protein drugs into lipid matrices may, however, be challenging, and different formulation approaches must be taken to achieve sufficient loading and preservation of native structure. The aim of the present study was to characterize insulin after complexation with biocompatible surfactants to improve loading into lipid-based DDS. Insulin–surfactant complexes were prepared by freeze-drying with distearyldimethylammonium bromide or soybean phospholipid as complexing surfactant and dimethyl sulfoxide (DMSO) as solvent. Significant change in secondary structure of insulin freeze dried from DMSO was observed using Fourier transform infrared spectroscopy. Changes were quantitatively smaller in the presence of surfactants, demonstrating both a stabilizing effect of surfactants, but also a nonnative secondary structure in the solid state. Finally, circular dichroism analysis of rehydrated complexes showed that the processing did not irreversibly alter the secondary structure of insulin. In short, the present study demonstrates changes in the secondary structure of insulin after freeze-drying from DMSO, constituting a potential generic issue with this technique for protein processing. In the specific case of insulin, the changes were found to be reversible, explaining the success of this strategy in previous studies.     

Evaluation of Skin Permeation of β-Blockers for Topical Drug Delivery

Purpose

β-Blockers have recently become the main form of treatment of infantile hemangiomas. Due to the potential systemic adverse effects of β-blockers, topical skin treatment of the drugs is preferred. However, the effect and mechanism of dosage form pH upon skin permeation of these weak bases is not well understood. To develop an effective topical skin delivery system for the β-blockers, the present study evaluated skin permeation of β-blockers propranolol, betaxolol, timolol, and atenolol.

Methods

Experiments were performed in side-by-side diffusion cells with human epidermal membrane (HEM) in vitro to determine the effect of donor solution pH upon the permeation of the β-blockers across HEM.

Results

The apparent permeability coefficients of HEM for the β-blockers increased with their lipophilicity, suggesting the HEM lipoidal pathway as the main permeation mechanism of the β-blockers. The pH in the donor solution was a major factor influencing HEM permeation for the β-blockers with a 2- to 4-fold increase in the permeability coefficient per pH unit increase. This permeability versus pH relationship was found to deviate from theoretical predictions, possibly due to the effective stratum corneum pH being different from the pH in the donor solution.

Conclusions

The present results suggest the possibility of topical treatment of hemangioma using β-blockers.     

In Vitro Evaluation of Dexamethasone-β-D-Glucuronide for Colon-Specific Drug Delivery

Dexamethasone--D-glucuronide is a potential prodrug for colonic delivery of the antiinflammatory corticosteroid dexamethasone. Previous studies [T. R. Tozer et al., Pharm. Res. 8:445–454 (1991)] indicated that a glucoside prodrug of dexamethasone was susceptible to hydrolysis in the upper gastrointestinal tract. Resistance of dexamethasone--D-glucuronide to hydrolysis in the upper gastrointestinal tract was therefore assessed. Conventional, germfree, and colitic rats were used to examine enzyme levels along the gastrointestinal tract to compare the stability of two model substrates (p-nitrophenyl--D-glucoside and --D-glucuronide) and to evaluate the prodrug dexamethasone--D-glucuronide. Hydrolytic activity was examined in the luminal contents, mucosa, and underlying muscle/connective tissues in all three types of rats. Enzymatic activity (-D-glucosidase and -D-glucuronidase) was greatest in the lumen of cecum and colon of conventional rats. In contrast, germ-free rats exhibited relatively high levels of -D-glucosidase activity (about 80% of total activity in the conventional rats) in the proximal small intestine (PSI) and the distal small intestine (DSI). Rats with induced colitis (acetic acid) showed reduced levels of luminal -D-glucuronidase activity in the large intestine; however, -D-glucosidase activity was relatively unchanged relative to that of the conventional rat. Mucosal -D-glucuronidase activity was significantly lower in the colitic rats compared with that in the conventional animals. Despite reduced luminal levels of -D-glucuronidase activity in the colitic rats, there was still a sharp gradient of activity between the small and the large intestines. Permeability of the glucoside and glucuronide prodrugs of dexamethasone through a monolayer of Caco-2 cells was relatively low compared to that of dexamethasone. The results indicate that dexamethasone--D-glucuronide should be relatively stable and poorly absorbed in the upper gastrointestinal tract. Once the compound reaches the large intestine, it should be hydrolyzed to dexamethasone and glucuronic acid. Specificity of colonic delivery in humans should be even greater due to lower levels of -D-glucuronidase activity in the small intestine compared with that in the laboratory rat.     

Gastrointestinal Responsive Polymeric Nanoparticles for Oral Delivery of Insulin: Optimized Preparation,Characterization, and In Vivo Evaluation

Gastrointestinal responsive polymeric nanospheres (NPs) based on hydroxypropyl methylcellulose phthalate were prepared using spontaneous emulsification solvent diffusion method for improved oral administration of insulin. The NPs prepared under optimized conditions have an encapsulation efficiency of 90% and a particle size of about 200 nm. In vitro drug release experiments demonstrated that the NPs exhibited a gradient release profile of loaded drug when the pH value gradually increased from 3.0 to 7.4. Enzyme resistance experiments showed that under simulated gastrointestinal conditions, the NPs protected more than 60% of the drug from being degraded by trypsin. The oral hypoglycemic experiments revealed that insulin-loaded NPs could significantly reduce blood glucose levels in diabetic rats with a relative bioavailability of 8.6%. Ex vivo imaging investigation of rat tissues showed that the drug-loaded NPs could promote the absorption of insulin in the ileum and colon. The work described here suggests that the gastrointestinal responsive polymeric NPs may be promising candidates for improving gastrointestinal tract delivery of hydrophilic biomacromolecules. Accordingly, the results indicated that hydroxypropyl methylcellulose phthalate NPs with gastrointestinal stimuli responsiveness could be a promising candidate for oral insulin delivery.     

Synthesis and Characterization of pH Tolerant and Mucoadhesive (Thiol–Polyethylene Glycol) Chitosan Graft Polymer for Drug Delivery

The objective of this study was to generate a water-soluble thiolated chitosan to enable the permeation-enhancing effect of chitosan at pH of at least 5.5 without losing the advantages of improved mucoadhesive properties. Therefore, the thiol-bearing polyoxyethylene ligand {O-(3-carboxylpropyl)-O′-[2-[3-mercaptopropionylamino)ethyl]-polyethyleneglycol} was conjugated via amide bond formation to the amino group of chitosan. Resulting novel chitosan derivative (Chito–PEG–SH) exhibited 250 μmol free thiol groups per gram polymer. By the attachment of the thiol-bearing PEG ligand, an improvement of permeation-enhancing effect on rat intestine (2.7-fold improvement) as well as on a Caco-2 monolayer model (1.9-fold improvement) could be found. Cytotoxicity studies on Caco-2 cells revealed no change in biocompatibility. Mucoadhesion was improved 3.1-fold by the formation of disulfide bonds with mucus glycoproteins. The mucoadhesive effect of Chito–PEG–SH turned out to be similar to thiolated chitosan and more pronounced than mucoadhesive properties of unmodified chitosan. The graft polymer is soluble in water and aqueous solutions over a broad pH range. In aqueous media, the novel polymer does not precipitate at pH of 8.6 or less. According to these results, Chito–PEG–SH might show potential as auxiliary agent in oral drug delivery where its solubility even up to pH 8 is likely beneficial.     

“Programmed Polymeric Devices” for Pulsed Drug Delivery

Pharmaceutical research strives to design drug delivery systems that respond to therapeutic needs. Considering the facts that physiologic parameters (e.g., heart rate, blood pressure, and plasma concentration of hormones, plasma proteins, and enzymes) display constancy over time, drug delivery systems with a constant release profile have been designed. However, because of circadian rhythms in physiologic parameters and pathologic conditions (e.g., asthma, angina pectoris), the conventional paradigm concerning drug concentrations "the flatter the better" may not be what the organism may need. Instead, to correlate with our biological needs, "precisely timed drug delivery," which could be accomplished with "programmable dosage forms," is required. Precisely timed drug delivery may maximize therapeutic efficacy, may minimize dose frequency, and may reduce toxicity by avoiding side effects and drug tolerance. This paper outlines the concepts that have been proposed to release drugs in a pulsed manner from pharmaceutical devices.     

Characterization of Substrates and Inhibitors for the In Vitro Assessment of Bcrp Mediated Drug–Drug Interactions

Purpose   In vitro assessment of drug candidates' affinity for multi-drug resistance proteins is of crucial importance for the prediction of in vivo pharmacokinetics and drug–drug interactions. To have well described experimental tools at hand, the objective of the study was to characterize substrates and inhibitors of Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp). Methods  Madin–Darbin canine kidney cells overexpressing mouse Bcrp (MDCKII-Bcrp) were incubated with various Bcrp substrates, or a mixture of substrate and inhibitor to either the apical (A) or basolateral (B) compartment of insert filter plates. Substrate concentrations in both compartments at time points t = 0 h and t = 2 h were determined by LC–MS/MS, and respective permeation coefficients (P _app) and efflux ratios were calculated. Results  The Bcrp inhibitor Ko143 blocked topotecan and ABZSO transport in a concentration-dependent manner. P-gp inhibitors ivermectin, LY335979, PSC833, and the P-gp/Bcrp inhibitor ritonavir did not influence Bcrp mediated topotecan transport, however, blocked ABZSO transport. Additionally, neither was ABZSO transport influenced by topotecan, nor topotecan transport by ABZSO. Conclusions  Data suggest different modes of substrate and inhibitor binding to Bcrp. In order to not overlook potential drug–drug interactions when testing drug candidates for inhibitory potential towards Bcrp, distinct Bcrp probe substrates should be used.     

Development of Orally Applicable,Combinatorial Drug–Loaded Nanoparticles for the Treatment of Fibrosarcoma

Nanoparticulate systems have been receiving a significant attention especially for the treatment of cancer but one of the main hurdles is to produce these developed and high-tech nanosystems in large quantities. Anticancer drug formulations are generally designed for parenteral administrations but oral administration is still the most convenient route. In this study, orally applicable nano-sized chitosan nanoparticles (NPs) were successfully prepared using Nano Spray Dryer. It is possible to produce these NPs in large quantities by simply increasing the processing time using the machine without changing any parameter. A chemotherapeutic agent (imatinib mesylate; IMA) and nonsteroidal anti-inflammatory drug (dexketoprofen trometamol) were loaded together in these NPs. NPs were also functionalized with polyethylene glycol and folic acid to obtain long circulating NPs and tumor targeting. The antitumoral activities of formulations showed that these developed NPs can enhance the effectiveness. Animal experiments were performed on fibrosarcoma-bearing mice model, and the treatment with 0.8 mg/μL/kg IMA-loaded chitosan NPs was found to be successful to slow down the growth of tumors. The tumor tissues were removed from the animals and enzymatic activities were evaluated. The inhibitory effect of tyrosine kinase was found to be enhanced from 36.4% to 68.4% when IMA was used in combination with dexketoprofen trometamol. Furthermore, all dried NPs were found to be stable for more than a year at 25°C. Presented results show that these developed combinatorial drug–loaded NPs can be used for the treatment of fibrosarcoma, and these data can provide an insight, new strategies for productions or alternatives in cancer treatment.     

Nanoparticles Based on Linear and Star-Shaped Poly(Ethylene Glycol)-Poly(ε-Caprolactone) Copolymers for the Delivery of Antitubulin Drug

Purpose

Biodegradable polymeric nanoparticles of different architectures based on polyethylene glycol-co-poly(ε-caprolactone) block copolymers have been loaded with noscapine (NOS) to study their effect on its anticancer activity. It was intended to use solubility of NOS in an acidic environment and ability of the nanoparticles to passively target drugs into cancer tissue to modify the NOS pharmacokinetic properties and reduce the requirement for frequent injections.

Methods

Linear and star-shaped copolymers were synthetized and used to formulate NOS loaded nanoparticles. Cytotoxicity was performed using a sulforhodamine B method on MCF-7 cells, while biocompatibility was determined on rats followed by hematological and histopathological investigations.

Results

Formulae with the smallest particle sizes and adequate entrapment efficiency revealed that NOS loaded nanoparticles showed higher extent of release at pH 4.5. Colloidal stability suggested that nanoparticles would be stable in blood when injected into the systemic circulation. Loaded nanoparticles had IC₅₀ values lower than free drug. Hematological and histopathological studies showed no difference between treated and control groups. Pharmacokinetic analysis revealed that formulation P1 had a prolonged half-life and better bioavailability compared to drug solution.

Conclusions

Formulation of NOS into biodegradable polymeric nanoparticles has increased its efficacy and residence on cancer cells while passively avoiding normal body tissues.

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Graphical Abstract ?

     

In Vitro–In Vivo Evaluation of an Oral Ghost Drug Delivery Device for the Delivery of Salmon Calcitonin

An orally administered site-specific Oral Ghost Drug Delivery (OGDD) device was developed and evaluated for the administration of salmon calcitonin. In vitro drug release studies have been undertaken using biorelevant media and aspirated gastrointestinal fluid from a large white pig in addition to characterization of a formulated trimethyl chitosan blend formulated and prepared into a loaded mini-pellet system. In vivo drug release analysis in a large white pig model has further been undertaken on the OGDD device and a commercial intramuscular injection to ascertain the release properties of the OGDD device in an animal model in comparison with the currently used treatment option for the administration of salmon calcitonin. Results of this study have detailed the success of the prepared system during both in vitro and in vivo analyses with the OGDD providing a greater control of release of salmon calcitonin when compared to the commercial product.     

Vancomycin–Triacetyl Cyclodextrin Interaction Products for Prolonged Drug Delivery

The aim of the present work was to investigate the capability of vancomycin (VCM) to interact with three hydrophobic cyclodextrins (TACD) (triacetyl alfa-, beta-, or gamma cyclodextrin) and the role played by the preparation technique in the formation of interaction products aimed at prolonging drug delivery for site-specific treatment of bone infections. Physical mixtures of VCM with triacetyl α-, β-, or γ-cyclodextrin in a 1:1 molar ratio were subjected to kneading, coevaporation, and spray drying from aqueous suspensions or hydroacetonic solution. Thermal behavior (TG, DSC), percent drug content (HPLC), and drug release (Franz cell) of VCM from the physical mixtures, and the relevant binary systems obtained by the various complexation methods were evaluated. All binary systems were characterized by having a particle size compatible with parenteral site-specific administration and with drug-loading efficiencies close to 100%, thus indicating the stability of vancomycin toward each and every complexation process. In vitro drug release measurements showed that the preparation technique plays a different role depending on the type of cyclodextrin used. In the kneading process, the binary system containing TAαCD is the most efficient in slowing down the VCM release. With the coevaporation technique, the system based on TAβCD was most effective in prolonging drug release. None of the triacetyl-cyclodextrins is suitable in prolonging VCM release upon spray drying from aqueous suspensions, because this preparation technique does not determine drug-cyclodextrin interaction. On the other hand, spray drying from hydroacetonic solutions always results in a reduction in drug release, linked to the formation of VCM-TACD interaction products and is particularly pronounced for the VCM-TAγCD interaction product. The unique properties of prolonging drug release and maintaining the antimicrobial activity of the native drug render such an interaction product the most promising candidate in the development of delivery systems intended for parenteral site-specific administration of VCM.     

What is a Suitable Dissolution Method for Drug Nanoparticles?

PURPOSE: Many existing and new drugs fail to be fully utilized because of their limited bioavailability due to poor solubility in aqueous media. Given the emerging importance of using nanoparticles as a promising way to enhance the dissolution rate of these drugs, a method must be developed to adequately reflect the rate-change due to size reduction. At present, there is little published work examining the suitability of different dissolution apparatus for nanoparticles. METHODS: Four commonly-used methods (the paddle, rotating basket and flow-through cell from the US Pharmacopia, and a dialysis method) were employed to measure the dissolution rates of cefuroxime axetil as a model for nanodrug particles. RESULTS: Experimental rate ratios between the nanoparticles and their unprocessed form were 6.95, 1.57 and 1.00 for the flow-through, basket and paddle apparatus respectively. In comparison, the model-predicted value was 7.97. Dissolution via dialysis was rate-limited by the membrane. CONCLUSIONS: The data showed the flow-through cell to be unequivocally the most robust dissolution method for the nanoparticulate system. Furthermore, the dissolution profiles conform closely to the classic Noyes-Whitney model, indicating that the increase in dissolution rate as particles become smaller results from the increase in surface area and solubility of the nanoparticles.     

Crucial Functionalizations of Carbon Nanotubes for Improved Drug Delivery: A Valuable Option?

Amidst the myriad of Drug Delivery Systems able to enhance delivery, absorption and intracellular uptake of a bioactive molecule while protecting it from deactivation, Carbon Nanotubes (CNTs) have emerged as a recent and promising option especially in cancer therapy. This is mainly due to their unique properties, which render them extremely versatile through the incorporation of several functional groups and targeting molecules at the same time, while their natural shape allows them to selectively penetrate across biological barriers in a non-invasive way. In this expert review we aim to evaluate whether this innovative material, once chemically-modified with suitable functionalizations, can be considered as a valuable system in comparison to the already existing nanodevices. This will include the estimation of the most recent advances in the field of nanotechnology, together with a cautious evaluation of potential risks and hazards associated with the extensive use of this fascinating, but still unknown, nanomaterial.     

Trimethyl Chitosan-Cysteine Nanoparticles for Systemic Delivery of TNF-α siRNA via Oral and Intraperitoneal Routes

Purpose

The lack of effective delivery vehicles impedes in vivo applications of siRNA. The trimethyl chitosan-cysteine (TC) nanoparticles (NPs) were developed for in vivo delivery of tumor necrosis factor α (TNF-α) siRNA via oral gavage and intraperitoneal injection.

Methods

The nanoparticles formulated from TC conjugate of 100, 200, and 500 kDa were prepared through ionic gelation with sodium tripolyphosphate, termed as TC100 NPs, TC200 NPs, and TC500 NPs, respectively. They were evaluated in terms of stability, siRNA protection, cellular uptake and TNF-α knockdown in peritoneal exudates macrophage cells (PECs), and in vivo TNF-α silencing in acute hepatic injury mice.

Results

TC100 NPs exhibited poor stability in simulated physiological environment compared to TC200 NPs and TC500 NPs. Compared to TC500 NPs, TC200 NPs could significantly enhance in vitro and in vivo cellular uptake by PECs and facilitate cytoplasmic siRNA release, resulting in high in vitro and in vivo TNF-α knockdown. Superior TNF-α suppressing level was obtained with TC200 NPs via oral gavage rather than intraperitoneal injection.

Conclusions

The efficacies of in vivo TNF-α silencing were related to the molecular weight of TC conjugate and the administration route, which would assist in the rational design of siRNA vehicles.     

Intranasal Delivery—Modification of Drug Metabolism and Brain Disposition

Intranasal route continues to be one of the main focuses of drug delivery research. Although it is generally perceived that the nasal route could avoid the first-pass metabolism in liver and gastrointestinal tract, the role of metabolic conversions in systemic and brain-targeted deliveries of the parent compounds and their metabolites should not be underestimated. In this commentary, metabolite formations after intranasal and other routes of administration are compared. Also, the disposition of metabolites in plasma and brain after nasal administrations of parent drugs, prodrugs and preformed metabolites will be discussed. The importance and implications of metabolism for future nasal drug development are highlighted.     

Potential of Cationic-Polymeric Nanoparticles for Oral Delivery of Naringenin: In Vitro and In Vivo Investigations

The objective of the study was to improve the bioavailability and anticancer potential of naringenin (NRG) by developing a drug-loaded polymeric nanodelivery system. NRG-loaded eudragit E100 nanoparticle (NRG-EE100-NPs) system was developed and physicochemically characterized. In vivo pharmacokinetic and in vitro cytotoxicity abilities of the NRG-EE100-NPs were investigated. In vivo anticancer activity was evaluated in murine BALB/c mice-bearing colorectal tumor. The NRG-EE100-NPs had an optimum mean particle size (430.42 ± 5.78 nm), polydispersity index (0.283 ± 0.089) with percent entrapment efficiency (68.83 ± 3.45%). The NRG-EE100-NPs demonstrated significant higher bioavailability (～96-fold; p <0.05) as well as cytotoxicity (～16-fold; p <0.001) as compared to free NRG. Furthermore, NRG-EE100-NPs indicated significant tumor suppression (p <0.01) subsequently improvement in survival rate compared to free NRG in vivo. Thus, the physicochemical properties and colorectal cancer efficacy of NRG were improved by successful encapsulating in cationic-polymeric nanoparticle system.     

Transdermal Delivery of Ketoprofen: The Influence of Drug–Dioleylphosphatidylcholine Interactions

Purpose Considering that most inflammatory diseases occur locally and near the body surface, transdermal delivery of non-steroidal anti-inflammatory drugs (NSAIDs) may be an interesting strategy for delivering these drugs directly to the diseased site. To optimize ketoprofen (KP) transdermal delivery we investigated the influence of dioleylphosphatidylcholine (DOPC) on skin permeation.Materials and Methods The formulations studied were: i) a physical mixture of KP and DOPC and ii) DOPC and KP complex, in a molar ratio of 1:3, obtained by dissolution of the components in chloroform followed by drying under a N₂ atmosphere. Both systems were dispersed in mineral oil and the in vitro percutaneous was assayed by absorption using a flow through diffusion cell. Differential Scanning Calorimetry (DSC) and ¹H NMR studies were carried out to characterize KP and DOPC interactions. Geometry optimizations using Density Functional Theory and semiempirical methods, as well as a flexible docking procedure were carried out to obtain a binding model for KP with DOPC. KP solubility and partition studies in the formulations, as well as skin irritation and hypersensitivity assays were also carried out.Results DSC determinations in the complex showed enthalpy and temperature depressions, indicating KP and DOPC interaction. In addition, dipole–dipole interactions between the KP carboxylic acid and OH groups in phospholipids were shown by ¹H NMR studies. Based on the NMR studies, a KP–DOPC binding model is proposed, in which KP is involved by the two long aliphatic chains of the phospholipid. Solubility studies indicated that DOPC improved drug solubility. KP permeation was enhanced by both formulations tested, but the complex also increased its skin uptake. Such behavior could be attributed to the solubilizing, melting and enhancing effects of DOPC. Skin irritation and hypersensitivity were not significantly changed compared to control, suggesting that the formulation may be therapeutically explored for KP transdermal delivery.