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Local anesthetics (LA), as part of multimodal analgesia, have garnered significant interest for their role in delaying the initiation of opioid therapy, reducing postoperative opioid usage, and mitigating both hospitalization duration and related expenses. Despite numerous endeavors to extend the duration of local anesthetic effects, achieving truly satisfactory long-acting analgesia remains elusive. Drawing upon prior investigations, vesicular phospholipid gels (VPGs) emerge as promising candidates for extended-release modalities in small-molecule drug delivery systems. Therefore, we tried to use the amphiphilicity of phospholipids to co-encapsulate levobupivacaine hydrochloride and meloxicam, two drugs with different hydrophilicity, to obtain a long-term synergistic analgesic effect. Initially, the physicochemical attributes of the formulation were characterized, followed by an examination of its in vitro release kinetics, substantiating the viability of extending the release duration of the dual drugs. Sequentially, in vivo investigations encompassing pharmacokinetic profiling and assessment of analgesic efficacy were undertaken, revealing a prolonged release duration of up to 120 h and attainment of optimal postoperative analgesia. Subsequently, inquiries into the mechanism underlying synergistic analgesic effects and safety evaluations pertinent to the delivery strategy were pursued. In summation, we successfully developed a promising formulation to achieve long-acting analgesia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

There is an unmet clinical need for new products to address the high percentage of the populous who present with periodontal diseases. Drug dose retention at the point of application would facilitate sustained release and more efficacious treatments. The aim of this study was to evaluate mucoadhesive polymeric thin films for simultaneous in situ delivery chlorhexidine and anti-inflammatory and analgesic drugs. Mucoadhesive thin films were prepared using a polymer mixture containing chlorhexidine (25 mg) ± diclofenac sodium (10 and 50 mg), and lidocaine hydrochloride (10 mg) or betamethasone dipropionate (10 and 50 mg). The films were assessed for in vitro drug release and localised tissue delivery, followed by determination of modulated prostaglandin E2 (PGE 2 ) levels in ex vivo tissue and cytotoxicity using a HaCaT keratinocyte cell line. Antibacterial activity of the chlorhexidine/diclofenac film was determined against planktonic and biofilm bacteria associated with periodontal disease and dental plaque. Chlorhexidine release was consistently low (up to 10% of initial loading) from all films, whereas the release of diclofenac, betamethasone and lidocaine exceeded 50% within 30 min. The 50 mg betamethasone film released up to 4-fold more than the 10 mg film. Statistically significant reduction of PGE 2 was observed in ex vivo porcine gingival tissue for films containing chlorhexidine with or without diclofenac, and betamethasone. No cytotoxicity was observed for any film, apart from 50 mg betamethasone at 24 h. Films loaded with chlorhexidine and diclofenac were inhibitory against relevant test bacteria. Between 3 and 6 log 10 reductions in bacterial cell recovery was observed after biofilm exposure to the chlorhexidine films irrespective of the presence of the anti-inflammatory or anaesthetic. This work demonstrated that thin film formulations have the potential to simultaneously counter key causative factors in periodontal diseases, namely associated bacteria biofilm and chronic local inflammation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The aim of the present work was to develop compound transdermal patch containing teriflunomide (TEF) and ketoprofen (KTP) using permeation enhancement strategy; reveal the molecular mechanism by which Azone (AZ) promoted transdermal absorption of compound patch through the enhancement of drug-drug intermolecular interaction. The formulation was optimized using in vitro skin permeation study and confirmed with pharmacodynamics study, anti-inflammatory study and analgesics study. Enhanced drug-drug interaction by AZ was characterized using FT-IR, 13 C NMR, molecular modeling and thermal analysis. The optimized formulation was composed of TEF (3%), KTP (2%), AZ (10%) and DURO-TAK® 87-4098 as adhesive matrix. The skin permeation amount of TEF-KTP combination was promoted by AZ about 1.9 times (594.2 ± 46.8 μg/cm 2 ) and 1.2 times (502.92 ± 24.0 μg/cm 2 ) compared with TEF-AZ and KTP-AZ individual patch. It was proved that the interaction between TEF and KTP via hydrogen bonding was further enhanced by AZ due to the increased molecular mobility of acrylate polymer (ΔT g  = -17.7 °C), which was proved by FTIR and 13 C NMR spectra. The enhanced drug-drug intermolecular interaction increased drug dispersed status and decreased the quantity of drug's hydrogen bonding site, thus increasing the drug release amount significantly. In conclusion, a compound transdermal patch containing KTP and TEF was developed successfully and a novel enhancement mechanism was clarified at molecular level, which provided reference for the development of novel compound transdermal patch., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Some recent studies have shown that pirfenidone (PFD) has favorable results in the healing process of the cornea. However, PFD in solution exhibits short half-life after topical application, and in this context, a liquid crystal nanoparticle system containing PFD (PFD-LCNPs) was developed. The nanoparticles were characterized by transmission electron microscopy, atomic force microscopy, small angle X-ray diffraction and polarized light microscopy. The PFD-LCNPs had particle size and zeta potential of 247.3 nm and -33.60 mV (stores at 4 °C), respectively, and 257.5 nm and -46.00 mV (stored at 25 °C), respectively. The pH of the formulation was 6.9 and the encapsulation efficiency was 35.9%. The in vitro release profiles indicated that PFD sustained release from PFD-LCNPs for up to 12 h. In vitro study of ocular irritation (HET-CAM test) concluded that components of the formulation are well tolerated for ocular administration. Corneal re-epithelialization time after chemical burning was significantly reduced in rabbits treated with PFD-loaded LCNPs when compared to the group treated with a vehicle. In addition, the anti-inflammatory action of pirfenidone was observed by reducing myeloperoxidase activity (MPO) and inflammatory cells in the histology of the tissues of animals treated with PFD-LCNPs. These findings indicated that the PFD-LCNPs might have the potential for effective ocular drug delivery., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The main purpose of this study was to develop gastroretentive tablets with floating and swelling properties for once-daily administration of pregabalin. The non-effervescent floating and swelling tablets were prepared using wet granulation and compaction, which are widely used and easily accessible. All formulations showed sustained release patterns and maintained buoyancy for over 24 h. The amount of hydroxypropyl methylcellulose and crospovidone were found to be critical factors affecting in vitro dissolution and floating properties of the prepared tablets. The optimized tablets containing 300 mg of pregabalin started to float within 3 min and swelled above 12.8 mm, the reported pyloric sphincter diameter during the fed state, in all dimensions including length, width, and thickness. In vivo results in beagle dogs indicated that the optimized formulations are suitable as once-daily dosage forms, and dose proportionality was observed in doses ranging from 75 to 300 mg. Additionally, the dogs administered with the formulation having poor in vitro gastroretentive properties showed highly variable and reduced extent of absorption, signifying the necessity of the gastroretentive drug delivery system. In conclusion, the developed non-effervescent floating tablets are promising candidates for once-daily delivery of pregabalin., (Copyright © 2018. Published by Elsevier B.V.)

Pregabalin is a promising drug for the treatment of neuropathic pain, a chronic disease affecting a large population needing long-term treatment. However, due to its short half-life, the commercial tablet has to be administered 2-3 times per day, with inconvenience for patient and fluctuations of plasma concentration. In this study, a gastro-floating drug delivery system of pregabalin was developed to prolong the gastric retention of drugs absorbed or act in stomach or upper gastrointestinal tract. First of all, it was proved that the drug was mainly absorbed in stomach and upper gastrointestinal tract. The final formulation was optimized in consideration of buoyancy and drug release profile. The gastro-floating tablet was prepared with hydroxypropyl methylcellulose (HPMC) as sustained-release matrix, lipophilic cetyl alcohol as floating-assistance agent and other excipients to achieve satisfying buoyancy and sustained release performance with mechanisms of diffusion and matrix erosion. Food exhibited significant effect on the pharmacokinetics of gastro-floating tablet and conventional capsule. Compared with conventional capsules, the relative bioavailability of gastro-floating tablet in fasted conditions or in fed conditions was only 62.47 ± 10.80% and 100.98 ± 17.25% respectively, even though the gastro-floating tablet obtained decreased C max and prolonged T max in fasted and fed conditions. Besides, good in vivo-in vitro correlation of the gastro-floating tablet was established. In summary, a gastro-floating tablet of pregabalin exhibiting desired buoyancy and release profiles was designed, and the tablet expressed significantly sustained-release behavior in fed conditions with good in vivo-in vitro correlation. The designed gastro-floating system is a promising choice for the patients to relieve neuropathic pain., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The purpose of this study was to evaluate the skin permeation of tricyclic antidepressants (TCAs) with propamine moiety to select candidates for the development of topical analgesics to treat cutaneous pain. We sought to establish the structure-permeation relationship (SPR) of topical TCAs. The lipophilicity, melting point, and aqueous solubility were determined to develop the physicochemical characterization. The TCA permeation into pig and nude mouse skins was estimated using Franz diffusion cell. TCAs and lidocaine were comparatively examined for cutaneous analgesia by pinprick assay. Cutaneous tolerance to TCAs was assessed using nude mouse skin. The skin deposition increased following the increase of lipophilicity after excluding the effect of solubility, with clomipramine exhibiting the highest skin retention. A contrary result was observed for TCA penetration into the receptor. Of the permeants tested, clomipramine demonstrated the best skin-targeting ability. Nortriptyline and clomipramine demonstrated selective uptake into the hair follicles, exhibiting a 2.5-fold higher follicular accumulation than desipramine. Replacement of nitrogen with carbon in the seven-member ring increased skin absorption. The tertiary amine TCAs demonstrated higher absorption than the secondary amine TCAs. The position of the double bond also affected skin transport. Topical clomipramine had a longer duration of analgesic action than lidocaine (240min versus 60min). Exploring the SPR revealed that clomipramine could be an analgesic candidate drug for future development., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Cutaneous iontophoretic delivery of μ-conotoxin CnIIIC (XEP), a potent peptide antagonist of the Na V 1.4 sodium channel, was investigated using porcine ear skin and validated using human abdominal skin. Initial results demonstrated that cutaneous deposition of XEP following iontophoresis was superior to passive delivery and increased with current density. XEP deposition after iontophoresis at 0.1, 0.3 and 0.5mA/cm 2 for 2h and 4h was 22.4±0.4, 34.5±1.4, 57.4±7.6μg/cm 2 and 30.6±5.4, 53.9±17.2, 90.9±30.8μg/cm 2 , respectively (cf. corresponding passive controls - 9.8±1.1 and 16.9±1.0μg/cm 2 ). Moreover, tape-stripping studies showed that XEP was mainly adsorbed on the skin surface when administered passively. Co-iontophoresis of acetaminophen demonstrated that XEP was present in the skin as it significantly reduced convective solvent flow as evidenced by the ∼7-fold decrease in acetaminophen permeation. Shorter duration iontophoresis (15, 30 and 60min) was performed and the effect of current density (0.1, 0.3 and 0.5mA/cm 2 ) and concentration (0.1 and 1mM) investigated. Skin deposition of XEP was already quantifiable after iontophoresis for 15min at the lower concentration. There was no statistically significant difference between XEP deposition in porcine and human skin. Confocal laser scanning microscopy enabled post-iontophoretic visualization of FITC-labelled XEP in the epidermis., (Copyright © 2016 Elsevier B.V. All rights reserved.)

According to previous studies reporting the anesthetic/analgesic action of oral topical doxepin administration, this study evaluated a model of buccal permeation to determine the depth of delivery of doxepin into excised porcine buccal mucosa following topical application of a saturated aqueous doxepin solution. Buccal mucosa permeation studies were performed using Franz diffusion cells. Cumulative amounts of doxepin permeated were plotted as a function of time. Kinetic permeation parameters as flux (Js), lag time (Tl) and permeability coefficient (Kp) were calculated. Theoretical human plasmatic steady-state doxepin concentration and drug retained in the tissue were also determined in order to evaluate its potential therapeutic use, central or peripheral. Finally, a histological evaluation of the buccal mucosa was performed to test potential damage due to the permeation phenomenon. Obtained results showed a poor aqueous doxepin permeation through buccal mucosa membrane (median parameters Js=34.79 μg/h, Kp=0.49×10(-3)cm/h and Tl=2.8h). Predicted doxepin plasma concentrations would reach 46 ng/mL, far from the required to have central nervous system activity as tricyclic agent. However, median doxepin amount remaining in the mucosa membrane was 0.24 μg/cm(2)/μg tissue, which evidenced a reservoir function of the buccal mucosa. Histologically, no structural damage was observed in the tissues. This study lays the foundation for further research within this area with a view to potentially adopting alternative strategies for enhanced buccal absorption of doxepin in clinical practice., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Drug delivery via the nasal route is gaining increasing interest over the last two decades as an alternative to oral or parenteral drug administration. In the current study an approach for rapid identification of relevant features, screening and in vivo verification of potential therapeutic agents for nasal delivery was carried out using "analgesic agents" as an example. Four such drug candidates (rizatriptan, meloxicam, lornoxicam and nebivolol) were initially identified as potentially viable agents based on their therapeutic use and physicochemical characteristics. An in vitro screening was then carried out using the Calu-3 cell line model. Based on the in vitro screening results and the reported pharmacokinetic and the stability data, meloxicam was predicted to be the most promising drug candidate and was subsequently verified using an in vivo animal model. The in vivo results showed that nasal administration of meloxicam was comparable to its intravenous administration, with respect to plasma drug concentration and AUC(0-2h). In addition, nasal absorption of meloxicam was much more rapid with higher plasma drug concentration and AUC(0-2h) than that of oral administration. The current approach appears to be capable of developing "analgesic agents" suitable for nasal delivery. Further studies are needed to prove the clinical advantage of the specific selected agent, meloxicam, by nasal administration in patients., (Copyright © 2011 Elsevier B.V. All rights reserved.)

A conductive polymer-hydrogel blend between sulfosalicylic acid-doped polypyrrole (PPy) and poly(acrylic acid) (PAA) was used as a carrier/matrix for the transdermal drug delivery under applied electrical field. PAA films and the blend films were prepared by solution casting with ethylene glycol dimethacrylate (EGDMA) as a cross-linking agent, followed by the blending of PPy particles and the PAA matrix. The effects of cross-linking ratio and electric field strength on the diffusion of the drug from PAA and PPy/PAA hydrogels were investigated using a modified Franz-diffusion cell with an acetate buffer of pH 5.5 and at 37 degrees C, for a period of 48h. The diffusion coefficient of the drug is calculated using the Higuchi equation, with and without an electric field, at various cross-linking ratios. The drug diffusion coefficient decreases with increasing drug size/mesh size ratio, irrespective of the presence of the conductive polymer as the drug carrier. The diffusion coefficient, at the applied electric field of 1.0V, becomes larger by an order of magnitude relative to those without the electric field.

Interest in intranasal (IN) administration as a non-invasive route for drug delivery continues to grow rapidly. The nasal mucosa offers numerous benefits as a target issue for drug delivery, such as a large surface area for delivery, rapid drug onset, potential for central nervous system delivery, and no first-pass metabolism. A wide variety of therapeutic compounds can be delivered IN, including relatively large molecules such as peptides and proteins, particularly in the presence of permeation enhancers. The current review provides an in-depth discussion of therapeutic aspects of IN delivery including consideration of the intended indication, regimen, and patient population, as well as physicochemical properties of the drug itself. Case examples are provided to illustrate the utility of IN dosing. It is anticipated that the present review will prove useful for formulation scientists considering IN delivery as a delivery route.

The Flynn database (n=97) for determining the effect of the physicochemical properties of solutes on their skin absorption has been edited to give a database for which the solubilities of the solutes in water, S(AQ), and their maximum fluxes from water through human skin in vitro, J(MAQ), are known or can be calculated (n=76). Data from the six major contributors to the original Flynn database have been included. Data for solutes, which were significantly ionized or for experiments using different thicknesses of skin were not excluded so that the edited database is as diverse as the original. The edited database was fit to five equations where the independent variables were solubility in octanol (S(OCT)) in water (S(AQ)) or molecular weight (MW), and combinations of those three variables; and the dependent variable was J(MAQ). The best fit was obtained from the Roberts-Sloan (RS) equation: logJ(MAQ)=x+ylogS(OCT)+(1-y)logS(AQ)-zMW, x=-3.00, y=0.73, z=0.0048, r(2)=0.934, S.D.=0.37 and F=274. This result is important because J (amount/area time) is the more clinically useful descriptor of permeation compared to P (distance/time); and because the identification of S(AQ) as a significant variable in predicting flux changes the design parameters for optimizing topical delivery of drugs from solubility in lipids (or partition coefficients between OCT and AQ, K(OCT:AQ)) and MW, to solubility in lipids, S(OCT), and in water, S(AQ), as well as MW.

The effect of iontophoresis combined with treatment of other physical enhancement methods such as electroporation, low frequency ultrasound, and erbium:YAG (yttrium-aluminum-garnet) laser on the transdermal delivery of sodium nonivamide acetate (SNA) was examined in this present study. Iontophoresis increased the transdermal flux of SNA in vitro as compared to the passive diffusion without any enhancement. Furthermore, iontophoresis was always the most potent enhancement method for SNA permeation among the physical enhancement methods tested. Pulsing of high voltages (electroporation) followed by iontophoresis did not result in increased transport over iontophoresis alone. However, electroporation shortened the onset of transdermal iontophoretic delivery of SNA. Pretreatment of low frequency ultrasound (sonophoresis) alone on skin did not increase the skin permeation of SNA. The combination of iontophoresis and sonophoresis increased transdermal SNA transport more than each method by itself. The enhancement of drug transport across shunt routes and reduction of the threshold voltage in the presence of an electric field may contribute to this synergistic effect. Use of an erbium:YAG laser was a good method for enhancing transdermal absorption of SNA because it allows precise control of stratum corneum (SC) removal, and this ablation of SC could be reversible to the original normal status. The combination of laser treatment and iontophoresis also synergized the skin permeation of SNA, possibly due to a gradual drop in the electric resistance of the skin. The results in this present study point out that the choice of certain conditions with suitable physical enhancement methods can induce a synergistic effect on transdermal delivery of SNA during iontophoresis.

A total of three free amine chitosans (CS J, CS L and CS H) and two soluble chitosan salts (CS G and CS HCl) were evaluated for their efficacy and safety as nasal absorption enhancers of peptides based on in situ nasal perfusion and subacute histological evaluation in rat. At 0.5% w/v, all chitosans were effective in enhancing the nasal absorption of [D-Arg(2)]-Kyotorphin, an enzymatically stable opioid dipeptide. The enhancing effect of the free amine chitosans increased as the pH was decreased from 6.0 to 4.0 (P<0.05). However, the pH effect was not significant for the two chitosan salts (P0.05), suggesting that their adjuvant activity may be less pH-dependent than the free amine form. CS J and CS G were subsequently selected for further studies. At only 0.02% w/v, their enhancing effect was already significant and comparable to that of 5% w/v hydroxypropyl-beta-cyclodextrin (HP-beta-CD). Both chitosans at 0.1% caused minimal release of total protein and phosphorus from the rat nasal mucosa, with the values similar to that of 5% HP-beta-CD. At 0. 5% the two chitosans also stimulated smaller release of lactate dehydrogenase, an intracellular enzyme used as marker of nasal membrane damage, than 1.25% dimethyl-beta-cyclodextrin. Morphological evaluation of the rat nasal mucosa following 2-week daily administration indicated that the two chitosans (1.0%) produced only mild to moderate irritation. In conclusion, both the free amine and the acid salt forms of chitosans are effective in enhancing the nasal absorption of [D-Arg(2)]-Kyotorphin and have potential for further studies as a safe and effective nasal absorption enhancer of peptide drugs.