Unsaturated Cyclic Ureas as New Nontoxic Biodegradable Transdermal Penetration Enhancers I: Synthesis

Wong, Osborne S.; Huntington, J.; Konishi, Ryoji; Rytting, J. Howard; Higuchi, Takeru

doi:10.1002/jps.2600771115

Cited by 29 publications

(7 citation statements)

References 4 publications

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“…These biodegradable cyclic urea analogs are composed of the 2,3-dihydroimidazol-2-one ring substituted by a hydroxyalkyl group [151][152][153]. The hydroxyl is connected to the hydrophobic chain via ester or carbonate bond.…”

Section: 3-dihydroimidazol-2-ones -Unsaturated Cyclic Ureasmentioning

confidence: 99%

Amphiphilic Transdermal Permeation Enhancers: Structure-Activity Relationships

Vávrová

Zbytovská²,

Hrabálek³

2005

CMC

112

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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.

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Section: 3-dihydroimidazol-2-ones -Unsaturated Cyclic Ureasmentioning

confidence: 99%

Amphiphilic Transdermal Permeation Enhancers: Structure-Activity Relationships

Vávrová

Zbytovská²,

Hrabálek³

2005

CMC

112

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“…The idea was to have more effective penetration enhancers which are decomposed by skin esterases after drug penetration promotion. Wong et al [49] synthesized urea derivatives with enhancing effects comparable to Azone.…”

Section: Urea and Derivativesmentioning

confidence: 99%

Overcoming the Stratum Corneum: The Modulation of Skin Penetration

Trommer

Neubert

2006

Skin Pharmacol Physiol

460

279

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It is preferred that topically administered drugs act either dermally or transdermally. For that reason they have to penetrate into the deeper skin layers or permeate the skin. The outermost layer of the human skin, the stratum corneum, is responsible for its barrier function. Most topically administered drugs do not have the ability to penetrate the stratum corneum. In these cases modulations of the skin penetration profiles of these drugs and skin barrier manipulations are necessary. A skin penetration enhancement can be achieved either chemically, physically or by use of appropriate formulations. Numerous chemical compounds have been evaluated for penetration-enhancing activity, and different modes of action have been identified for skin penetration enhancement. In addition to chemical methods, skin penetration of drugs can be improved by physical options such as iontophoresis and phonophoresis, as well as by combinations of both chemical and physical methods or by combinations of several physical methods. There are cases where skin penetration of the drug used in the formulation is not the aim of the topical administration. Penetration reducers can be used to prevent chemicals entering the systemic circulation. This article concentrates on the progress made mainly over the last decade by use of chemical penetration enhancers. The different action modes of these substances are explained, including the basic principles of the physical skin penetration enhancement techniques and examples for their application.

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“…21 Azone analogues with the potential for biodegradability have also been actively pursued. 22,23 In an attempt to acheive high flux-enhancing activity and potential biodegradibility, we have incorporated an ester moiety into an Azone-like structure.…”

mentioning

confidence: 99%

Synthesis and in Vitro Transdermal Penetration Enhancing Activity of Lactam N-Acetic Acid Esters

Michniak¹,

Player²,

Sowell³

1996

Journal of Pharmaceutical Sciences

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A homologous series of N-acetic acid esters of 2-pyrrolidinone and 2-piperidinone has been prepared and evaluated for its ability to enhance the skin content and flux of hydrocortisone 21-acetate in hairless mouse skin in vitro. Enhancement ratios (ER) were determined for flux (J), 24-hour diffusion cell receptor cell concentrations (Q24), and 24-h full-thickness mouse skin steroid content (SC) and compared to control values (no enhancer present). In addition, in an attempt to abrogate toxicity, these dermal penetration enhancers were designed to have the potential for biodegradation by dermal esterases. 2-Oxopyrrolidine-alpha acetic acid dodecyl ester (5) showed the highest enhancement ratios for J (ER 67.33) and Q24 (ER 180.66). 2-Oxopiperidine-alpha-acetic acid decyl ester (10) showed a high Q24 (ER 162.07) but a lower J (ER 12.67). 2-Oxopyrrolidine-alpha-acetic acid decyl ester (3) showed the highest enhancement ratio for SC (ER 8.7). The ER Q24 for 3, 5 and 10, as well as other lactam N-acetic acid esters in this work, were significantly higher than the ER found using Azone as enhancer.

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Unsaturated Cyclic Ureas as New Nontoxic Biodegradable Transdermal Penetration Enhancers I: Synthesis

Cited by 29 publications

References 4 publications

Amphiphilic Transdermal Permeation Enhancers: Structure-Activity Relationships

Amphiphilic Transdermal Permeation Enhancers: Structure-Activity Relationships

Overcoming the Stratum Corneum: The Modulation of Skin Penetration

Synthesis and in Vitro Transdermal Penetration Enhancing Activity of Lactam N-Acetic Acid Esters

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