skin permeation enhancers Dotaz Zobrazit nápovědu
Transdermal drug delivery is an attractive non-invasive method offering numerous advantages over the conventional routes of administration. The main obstacle to drug transport is, however, the powerful skin barrier that needs to be modulated, for example, by transdermal permeation enhancers. Unfortunately, there are still only a few enhancers showing optimum properties including low toxicity and reversibility of enhancing effects. For this reason, we investigated a series of new N-alkylmorpholines with various side chains as potential enhancers in an in vitro permeation study, using three model permeants (theophylline, indomethacin, diclofenac). Moreover, electrical impedance, transepidermal water loss, cellular toxicity and infrared spectroscopy measurements were applied to assess the effect of enhancers on skin integrity, reversibility, toxicity and enhancers' mode of action, respectively. Our results showed a bell-shaped relationship between the enhancing activity and the hydrocarbon chain length of the N-alkylmorpholines, with the most efficient derivatives having 10-14 carbons for both transdermal and dermal delivery. These structures were even more potent than the unsaturated oleyl derivative. The best results were obtained for indomethacin, where particularly the C10-14 derivatives showed significantly stronger effects than the traditional enhancer Azone. Further experiments revealed reversibility in the enhancing effect, acceptable toxicity and a mode of action based predominantly on interactions with stratum corneum lipids.
- Publikační typ
- časopisecké články MeSH
It is proposed that the low skin permeation potential of palonosetron could be enhanced by the inclusion of chemical permeation enhancers. The objective of this study is to evaluate the influence of various chemical enhancers on the transdermal permeation of palonosetron. Different drugs in adhesive transdermal patches (F1–F5) were prepared using five pressure sensitive adhesives; Duro-Tak 87-4098, Duro-Tak 87-2074, Duro-Tak 87-900A, Duro-Tak 87-9301 and Duro-Tak 87-2287. Patches prepared using Duro-Tak 87-9301 (F5) was further combined with four well-known chemical enhancers. The influence of permeation enhancers (propylene glycol, diethylene glycol monoethyl ether, Tween 80 and oleic acid) on the transdermal flux was evaluated ex vivo. Release of the drug from fabricated patches was carried out for a period of 6 h. Greater amount of drug (12% w/w) was incorporated in the patches prepared using Duro-Tak 87-9301 (F5). Incorporation of skin permeation enhancers significantly (P < 0.001) improves the transdermal flux of palonosetron. Among the permeation enhancers, propylene glycol (5% w/w) shows highest permeation (53.12 ± 5.62 μg/cm2/h), which is ∼4 folds higher than control. Biphasic drug release was noticed in the prepared patches and the rate of release was relatively high with patch F7. This study reveals that the optimized transdermal system with propylene glycol as permeation enhancers can provide effective therapeutic level of palonosetron.
- Klíčová slova
- enhancery, urychlovače permeace,
- MeSH
- adjuvancia farmaceutická * klasifikace MeSH
- kožní absorpce * MeSH
- nauzea farmakoterapie chemicky indukované MeSH
- palonosetron * aplikace a dávkování farmakokinetika MeSH
- potkani Wistar MeSH
- propylenglykol MeSH
- protinádorové látky škodlivé účinky MeSH
- techniky in vitro MeSH
- transdermální náplast MeSH
- uvolňování léčiv MeSH
- zvířata MeSH
- zvracení farmakoterapie chemicky indukované MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
Introduction: Transdermal drug delivery has several clinical benefits over conventional routes of drug administration. To open the transdermal route for a wider range of drugs, including macromolecules, numerous physical and chemical techniques to overcome the natural low skin permeability have been developed.Areas covered: This review focuses on permeation enhancers (penetration enhancers, percutaneous absorption promoters or accelerants), which are chemicals that increase drug flux through the skin barrier. First, skin components, drug permeation pathways, and drug properties are introduced. Next, we discuss properties of enhancers, their various classifications, structure-activity relationships, mechanisms of action, reversibility and toxicity, biodegradable enhancers, and synergistic enhancer combinations.Expert opinion: Overcoming the remarkable skin barrier properties in an efficient, temporary and safe manner remains a challenge. High permeation-enhancing potency has long been perceived to be associated with toxicity and irritation potential of such compounds, which has limited their further development. In addition, the complexity of enhancer interactions with skin, formulation and drug, along with their vast chemical diversity hampered understanding of their mechanisms of action. The recent development in the field revealed highly potent yet safe enhancers or enhancer combinations, which suggest that enhancer-aided transdermal drug delivery has yet to reach its full potential.
- MeSH
- aplikace kožní MeSH
- kožní absorpce * MeSH
- kůže metabolismus MeSH
- léčivé přípravky aplikace a dávkování metabolismus MeSH
- lékové transportní systémy MeSH
- lidé MeSH
- permeabilita MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Publikační typ
- abstrakt z konference MeSH
Transdermal drug delivery offers numerous advantages over conventional routes of administration; however, poor permeation of most drugs across the skin barrier constitutes a serious limitation of this methodology. One of the approaches used to enlarge the number of transdermally-applicable drugs uses permeation enhancers. These compounds promote drug permeation through the skin by a reversible decrease of the barrier resistance. Enhancers can act on the stratum corneum intracellular keratin, influence desmosomes, modify the intercellular lipid domains or alter the solvent nature of the stratum corneum. Even though, hundreds of substances have been identified as permeation enhancers to date, yet our understanding of the structure-activity relationships is limited. In general, enhancers can be divided into two large groups: small polar solvents, e.g. ethanol, propylene glycol, dimethylsulfoxide and amphiphilic compounds containing a polar head and a hydrophobic chain, e.g. fatty acids and alcohols, 1-dodecylazepan-2-one (Azone), 2-nonyl-1,3-dioxolane (SEPA 009), and dodecyl-2-dimethylaminopropanoate (DDAIP). In this review we have focused on structure-activity relationships of amphiphilic permeation enhancers, including the properties of the hydrophobic chains, e.g. length, unsaturation, and branching, as well as the polar heads characteristics, e.g. hydrogen bonding ability, lipophilicity, and size. We present over 180 examples of enhancers with different polar head to illustrate the structural requirements and the possible role of the polar head. We have given an overview of the methods used for investigation of the mechanisms of permeation enhancement, namely differential scanning calorimetry (DSC), infrared (IR) and Raman spectroscopy, X-ray diffraction and future perspectives in this field. Furthermore, biodegradability and chirality of the enhancers are discussed.
- MeSH
- absorpce účinky záření MeSH
- aplikace kožní MeSH
- ceramidy aplikace a dávkování chemie MeSH
- farmaceutická chemie MeSH
- financování organizované MeSH
- hydrofobní a hydrofilní interakce MeSH
- keratiny metabolismus MeSH
- kůže metabolismus účinky léků MeSH
- lékové transportní systémy MeSH
- lipidy chemie MeSH
- permeabilita účinky léků MeSH
- rozpouštědla chemie MeSH
- vodíková vazba MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
Transdermal permeation enhancers are compounds that temporarily decrease skin barrier properties to promote drug flux. In this study, we investigated enhancers with amino acids (proline, sarcosine, alanine, β-alanine, and glycine) attached to hydrophobic chain(s) via a biodegradable ester link. The double-chain lipid-like substances displayed no enhancing effect, whereas single-chain substances significantly increased skin permeability. The proline derivative l-Pro2 reached enhancement ratios of up to 40 at 1% concentration, which is higher than that of the well-established and standard enhancers Azone, DDAIP, DDAK, and Transkarbam 12. No stereoselectivity was observed. l-Pro2 acted synergistically with propylene glycol. Infrared studies revealed that l-Pro2 forms a separate liquid ordered phase in the stratum corneum lipids and has no significant effect on proteins. l-Pro2 action was at least partially reversible as measured by skin electrical impedance. Toxicity in keratinocyte (HaCaT) and fibroblast (3T3) cell lines showed IC(50) values ranging from tens to hundreds of μM, which is comparable with standard enhancers. Furthermore, l-Pro2 was rapidly decomposed in plasma. In vivo transdermal absorption studies in rats confirmed the enhancing activity of l-Pro2 and suggested its negligible skin toxicity and minimal effect on transepidermal water loss. These properties make l-Pro2 a promising candidate for potential clinical use.
- MeSH
- aminokyseliny chemie metabolismus farmakologie toxicita MeSH
- aplikace kožní MeSH
- buněčné linie MeSH
- buňky 3T3 MeSH
- keratinocyty účinky léků metabolismus MeSH
- kožní absorpce účinky léků MeSH
- krevní plazma metabolismus MeSH
- krysa rodu rattus MeSH
- kůže účinky léků metabolismus MeSH
- lidé MeSH
- myši MeSH
- permeabilita účinky léků MeSH
- prasata MeSH
- prolin analogy a deriváty metabolismus farmakologie toxicita MeSH
- stabilita léku MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Transkarbams (T) represent novel group of highly active, non-toxic transdermal permeation enhancers. This study was focused on the influence of small symmetrical terminal branching on their enhancing activity. Series of T with terminal methyl or ethyl branching was prepared and their permeation-enhancing activity was compared to that of their linear analogues. The results showed completely a different behaviour from similarly branched alcohols, supporting the key role of the ammonium-carbamate polar head in the enhancing activity of T.
In order to investigate the effect of branching and cyclization in the hydrophobic part of skin permeation enhancers, 17 novel branched-chain and cyclic 6-aminohexanoic acid esters were prepared. Their permeation enhancing activity was evaluated in vitro using human skin and theophylline as a model drug, and compared to that of the corresponding linear-chain analogues. The results showed that chain branching and cyclization has a negative influence on the enhancing activity of 6-aminohexanoates. For example, the enhancement ratios (ERs) of dodecan-1-yl, dodecan-2-yl, dodecan-4-yl, and cyclododecyl ester were 39.7, 29.3, 3.1, and 2.2, respectively. No significant change in the optimum length of the chain was observed. Dodecan-2-yl 6-aminohexanoate, the most active branched derivative, still maintains a remarkable enhancing activity (ER 29.3). Presumably, the relatively small degree of branching of these molecules does not prevent them from interacting with the lipid components of the stratum corneum. However, a higher degree of branching, cyclization of the chain, and presence of an aromatic ring resulted in a loss of activity. (c) 2005 Wiley-Liss, Inc.
- MeSH
- alkoholy chemie MeSH
- aminokapronáty MeSH
- estery farmakologie chemie MeSH
- financování vládou MeSH
- kožní absorpce účinky léků MeSH
- kyselina 6-aminokapronová farmakologie chemie MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- techniky in vitro MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
The activity of transdermal permeation enhancers is usually evaluated in vitro on human or animal skin, but skin samples can be hard to source and highly variable. To provide a more consistent basis for evaluating the activity of permeation enhancers, we prepared relatively simple and inexpensive artificial membranes that imitate the stratum corneum (SC) lipid matrix. Our membranes were composed of stearic acid, cholesterol, cholesterol sulfate and a ceramide (CER) component consisting of N-2-hydroxystearoyl phytosphingosine (CER[AP]) and/or N-stearoyl phytosphingosine (CER[NP]). First, the permeation of theophylline (TH) and indomethacin (IND) through these membranes was compared with their permeation through porcine skin. Because the mixed CER[AP]/[NP] membrane gave the closest results to skin, this membrane was then used to test the effects of two permeation enhancers: N-dodecyl azepan-2-one (Azone) and (S)-N-acetylproline dodecyl ester (L-Pro2). Both enhancers significantly increased the flux of TH and IND through the skin and, even more markedly, through the lipid membrane, L-Pro2 having a stronger effect than Azone. Thus, our simplified model of the SC lipid membrane based on phytosphingosine CERs appears to be suitable for mimicking skin permeation.
- MeSH
- aplikace kožní MeSH
- azepiny farmakologie MeSH
- ceramidy metabolismus MeSH
- cholesterol metabolismus MeSH
- indomethacin farmakologie MeSH
- kožní absorpce účinky léků MeSH
- kůže metabolismus MeSH
- kyseliny stearové metabolismus MeSH
- lidé MeSH
- membránové lipidy metabolismus MeSH
- membrány umělé MeSH
- permeabilita účinky léků MeSH
- prasata MeSH
- theofylin farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
