Formulation, physico-chemical characterization and biological testing of biocompatible microemulsions for dermal and transdermal delivery of aceclofenac

Nesteroidni antiinflamatorni lekovi (NSAIL) su heterogena grupa lekovitih supstanci sa antiinflamatornim, antipiretičkim i analgetskim delovanjem. Iako postoji više od 50 različitih NSAIL na svetskom tržištu, stalno istraživanje i razvoj novih lekovitih supstanci ove terapijske grupe je posledica njihovog nepovoljnog farmakokinetičkog profila (npr. kratko poluvreme eliminacije) i/ili ispoljavanja neželjenih efekata (npr. na nivou gastrointestinalnog trakta). Aceklofenak je indikovan za oralnu primenu u terapiji reumatoidnih bolesti, kao i u terapiji drugih upalnih i bolnih stanja. I pored prednosti u odnosu na ostale lekovite supstance iz ove grupe, hronična oralna primena aceklofenaka može dovesti do pojave neželjenih efekata koji su karakteristični i za ostale NSAIL, te se nameće potreba za prevazilaženjem ovih problema primenom farmaceutsko-tehnoloških pristupa i/ili drugim putem primene. Jedan od načina za smanjenje neželjenih efekata i zaobilaženje metabolizma prvog prolaza je lokalna primena aceklofenaka u terapiji reumatoidnih bolesti. Da bi koncentracija lokalno primenjenog aceklofenaka bila dovoljna za ispoljavanje kliničkog efekta, neophodno je prevazići stratum corneum, primarnu barijeru za difuziju lekovitih supstanci u kožu. Koloidni nosači tipa mikroemulzija su perspektivni nosači lekovitih supstanci, čijom se primenom može poboljšati dermalna/transdermalna isporuka, a time i lokalna i/ili sistemska raspoloživost. Sa druge strane, neophodno je posvetiti posebnu pažnju izboru ekscipijenasa, kako sa aspekta bezbednosti/iritacije, tako i sa aspekta njihovog potencijalnog uticaja na dermalnu/transdermalnu isporuku lekovite supstance. Saharozni estri su nejonski surfaktanti, a njihove osobine poput biokompatibilnosti, biodegradabilnosti, niskog rizika da dovedu do iritacije, i potencijala da deluju kao pojačivači penetracije, predstavljaju značajne prednosti ovih surfaktanata u odnosu na tradicionalno korišćene, sintetske, etoksilovane surfaktante. Imajući to u vidu, osnovni cilj istraživanja ove doktorske disertacije predstavlja proučavanje molekularnih mehanizama kojima saharozni estri, sa različitom dužinom lipofilnog lanca, povećavaju penetraciju lekovitih supstanci...Despite the diversity of the chemical structures, non-steroidal anti-inflammatory drugs (NSAIDs) share the same activity, such as analgesic, antipyretic and anti-inflammatory. Interestingly, there are more than 50 different NSAIDs on the global market – the continuous research and development of new active substances from this therapeutic group is related to their unfavourable pharmacokinetic properties (e.g. short half-life) or is associated with a broad spectrum of adverse reactions (e.g. gastrointestinal side effects). Aceclofenac is indicated in the therapy of rheumatoid diseases, as well as in the symptomatic therapy of pain and inflammation. Although effective and relatively safe, chronic oral aceclofenac administration may cause systemic side effects typical of other NSAIDs, which warrants the search for a new route of its administration and/or implementation of pharmaceutical-technological approaches in the therapy of musculoskeletal disorders, in order to decrease the incidence of adverse reactions, as well as to avoid the first-pass metabolism. The crucial step during any topical NSAID therapy is the ability of drug to overcome the outermost layer of the skin – stratum corneum, as a critical barrier for penetration of an active through the skin in sufficiently high amount to exert its clinical effect. Microemulsions are colloidal systems that are currently of pharmaceutical interest as promising vehicles which can improve dermal/transdermal drug delivery, and thus, its local/systemic bioavailability. However, the choice of excipient is one of the key factors in preformulation studies, due to their potential influence on skin tolerability, as well as their ability to act as penetration enhancers. Described as very mild and nonirritant with regard to dermatological properties, sucrose esters are of growing research interest, with promising features of low skin sensitization potential and enhancing skin penetration effect, as well as with a high environmental compatibility, all of which may be distinct advantages when compared to traditionally used synthetic ethoxylated surfactants..

Alkyl polyglucoside vs. ethoxylated surfactant-based microemulsions as vehicles for two poorly water-soluble drugs: physicochemical characterization and in vivo skin performance

Two types of biocompatible surfactants were evaluated for their capability to formulate skin-friendly/non-irritant microemulsions as vehicles for two poorly water-soluble model drugs differing in properties and concentrations: alkyl polyglucosides (decyl glucoside and caprylyl/capryl glucoside) and ethoxylated surfactants (glycereth-7-caprylate/caprate and polysorbate 80). Phase behavior, structural inversion and microemulsion solubilization potential for sertaconazole nitrate and adapalene were found to be highly dependent on the surfactants structure and HLB value. Performed characterization (polarized light microscopy, pH, electrical conductivity, rheological, FTIR and DSC measurements) indicated a formulation containing glycereth-7-caprylate/caprate as suitable for incorporation of both drugs, whereas alkyl polyglucoside-based systems did not exhibit satisfying solubilization capacity for sertaconazole nitrate. Further, monitored parameters were strongly affected by sertaconazole nitrate incorporation, while they remained almost unchanged in adapalene-loaded vehicles. In addition, results of the in vivo skin performance study supported acceptable tolerability for all investigated formulations, suggesting selected microemulsions as promising carriers worth exploring further for effective skin delivery of model drugs

Natural Surfactants-Based Micro/Nanoemulsion Systems for NSAIDs- Practical Formulation Approach, Physicochemical and Biopharmaceutical Characteristics/Performances

Considering the superior advantages over traditional formulation approaches, micro/nanoemulsions represent very attractive carriers worth exploring for improving dermal/transdermal delivery of NSAIDs. Currently, natural-origin sucrose esters are of increasing interest for research community, due to their high environmental compatibility, low skin sensitization potential, and skin penetration enhancement. In this context, the present chapter provides an overview of sucrose esters' potential in the development of biocompatible micro/nanoemulsions for topical administration of NSAIDs. The formation and performances of sucrose ester-based micro/nanoemulsions are governed by numerous factors which should be carefully considered, such as (1) chain length and monoester content of the sucrose esters, (2) nature and concentration of the cosurfactant, oil, and aqueous phase, (3) the components' weight ratio, and (4) physicochemical characteristics of NSAID. Therefore, here we review the key researches regarding NSAID-loaded sucrose ester-based micro/nanoemulsions, starting from the formulation design consideration, through physicochemical characterization and dermal/transdermal availability assessment of developed systems

Sucrose esters as biocompatible surfactants for penetration enhancement: An insight into the mechanism of penetration enhancement studied using stratum corneum model lipids and Langmuir monolayers

Up to now, the molecular mechanism of the penetration enhancing effect of sucrose esters (SEs) on stratum corneum (SC) has not been explained in details. In this study, variety of surface sensitive techniques, including surface pressure-area (pi-A) isotherms, infrared reflection-absorption spectroscopy (IRRAS), and Brewster angle microscopy (BAM), have been used to investigate interactions between SEs and SC intercellular lipids. A monolayer of the mixture of ceramide AS C18:18, stearic acid and cholesterol in the molar ratio of 1:1:0.7 on an aqueous subphase is a good model to mimic a single layer of intercellular SC lipids. The pi-A isotherms of mixed monolayers and parameters derived from the curves demonstrated the interaction between nonionic surfactants such as SEs and SC lipids. With increasing SE concentration, the resultant monolayer films became more fluid and better compressible. IRRAS measurements showed that SEs disordered the acyl chains of SC lipids, and the BAM images demonstrated the modification of the domain structures in SC monolayers. Longer chain-SE has a stronger disordering effect and is better miscible with ceramides in comparison to SE with a shorter hydrophobic part. In conclusion, this study demonstrates the disordering effect of SEs on the biomimetic SC model, pointing out that small changes in the structure of surfactant may have a strong influence on a penetration enhancement of lipophilic drugs through intercellular lipids of skin

Sucrose ester-based biocompatible microemulsions as vehicles for aceclofenac as a model drug: formulation approach using D-optimal mixture design

We assessed the functionality of sucrose esters (sucrose laurate, myristate, palmitate, and stearate), relatively innocuous nonionic surfactants, in formulation of biocompatible microemulsions. The putative influence of surfactant structure on the extension of microemulsion region was explored through the construction of the pseudo-ternary phase diagrams for the isopropyl myristate/sucrose ester-isopropyl alcohol/water system, using the titration method and mixture experimental approach. Minor changes in surfactant tail length strongly affected the microemulsion area boundaries. D-optimal mixture design proved to be highly applicable in detecting the microemulsion regions. Examination of conductivity, rheology, and thermal behavior of the selected sucrose laurate and sucrose myristate-based microemulsions, upon dilution with water, indicated existence of percolation threshold and suggested the phase inversion from water-in-oil to oil-in-water via a bicontinuous structure. Atomic force micrographs confirmed the suggested type of microemulsions and were valuable in further exploring their inner structure. The solubilization capacity of aceclofenac as a model drug has decreased as the water volume fraction in microemulsion increased. High surfactant concentration and the measured solubility of aceclofenac in microemulsion components suggested that the interfacial film may mostly contribute to aceclofenac solubilization

Biocompatible microemulsions of a model NSAID for skin delivery: A decisive role of surfactants in skin penetration/irritation profiles and pharmacokinetic performance

To elaborate the decisive role of surfactants in promotion of aceclofenac' skin absorption, potentially avoiding irritation, we developed non-ionic microemulsions varying natural or synthetic surfactants: sucrose esters (laurate or myristate) vs. polysorbate 80. A comprehensive physicochemical characterization indicated no significant influence of the solubilized nonsteroidal anti-inflammatory drug on the bicontinuous structure of blank formulations. To evaluate skin tolerability of isopropyl alcohol, a sucrose ester-based microemulsion containing transcutol P as a cosurfactant was also developed. The measured skin parameters strongly depended on the (co)surfactant type, showing higher compatibility of the microemulsions containing sucrose ester and isopropyl alcohol. In vitro release results, in vivo tape stripping and pharmacokinetics in rats confirmed superiority of the sucrose ester-over polysorbate-based microemulsions (total amounts of aceclofenac penetrated 60.81 +/- 5.97 and 60.86 +/- 3.67 vs. 27.00 +/- 5.09 mu g/cm(2), and its maximum plasma concentrations 275.57 +/- 109.49 and 281.31 +/- 76.76 vs. 150.23 +/- 69.74 ng/ml for sucrose laurate- and myristate- vs. polysorbate 80-based microemulsions, respectively). Hence, sugar-based excipients increased delivery of aceclofenac through stratum corneum by increasing its fluidity, showing overall more satisfying safety profiles. In conclusion, sucrose ester-based microemulsions proved to be promising carriers for dermal/transdermal aceclofenac delivery

Tacrolimus loaded biocompatible lecithin-based microemulsions with improved skin penetration: Structure characterization and in vitro/in vivo performances

In order to improve skin penetration of tacrolimus we aimed to develop potentially non-irritant, lecithin-based microemulsions containing ethanol, isopropanol and/or propylene glycol as cosurfactants, varying caprylic/capric triglycerides and propylene glycol monocaprylate as oil phase. The influence of excipients on the size of microemulsion region in pseudo-ternary phase diagrams and their ability to form different types of microemulsions was evaluated. The comprehensive physicochemical characterization of microemulsions and the evaluation of their structure was performed, while the localization of tacrolimus in microemulsions was further investigated using electron paramagnetic resonance spectroscopy. Moreover, stability studies proved no change in tacrolimus content during one year of storage at room temperature. In addition, in vivo skin performance indicated no skin irritation potential of blank microemulsions, whereas in vitro release testing using Franz diffusion cells showed superior release rate of tacrolimus from microemulsions (0.98 +/- 0.10 and 0.92 +/- 0.11 mu g/cm(2)/h for two bicontinuous and 1.00 +/- 0.24 mu g/cm(2)/h for oil-in-water microemulsion) compared to referent Protopic ointment (0.15 +/- 0.08 mu g/cm(2)/h). Furthermore, ex vivo penetration assessed through porcine ear skin using tape stripping, confirmed superiority of two microemulsions related to the reference, implying developed microemulsions as promising carriers for dermal delivery of tacrolimus

Alkyl polyglucoside vs. ethoxylated surfactant-based microemulsions as vehicles for two poorly water-soluble drugs: physicochemical characterization and in vivo skin performance

Two types of biocompatible surfactants were evaluated for their capability to formulate skin-friendly/non-irritant microemulsions as vehicles for two poorly water-soluble model drugs differing in properties and concentrations: alkyl polyglucosides (decyl glucoside and caprylyl/capryl glucoside) and ethoxylated surfactants (glycereth-7-caprylate/ caprate and polysorbate 80). Phase behavior, structural inversion and microemulsion solubilization potential for sertaconazole nitrate and adapalene were found to be highly dependent on the surfactants structure and HLB value. Performed characterization (polarized light microscopy, pH, electrical conductivity, rheological, FTIR and DSC measurements) indicated a formulation containing glycereth- 7-caprylate/caprate as suitable for incorporation of both drugs, whereas alkyl polyglucoside-based systems did not exhibit satisfying solubilization capacity for sertaconazole nitrate. Further, monitored parameters were strongly affected by sertaconazole nitrate incorporation, while they remained almost unchanged in adapalene-loaded vehicles. In addition, results of the in vivo skin performance study supported acceptable tolerability for all investigated formulations, suggesting selected microemulsions as promising carriers worth exploring further for effective skin delivery of model drugs