Synthesis and Enhancing Effect of Transkarbam 12 on the Transdermal Delivery of Theophylline, Clotrimazole, Flobufen, and Griseofulvin

Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, 50012 Hradec Králové, Czech Republic.
Pharmaceutical Research (Impact Factor: 3.42). 06/2006; 23(5):912-9. DOI: 10.1007/s11095-006-9782-y
Source: PubMed


Dodecyl-6-aminohexanoate (DDEAC) is a transdermal permeation enhancer with excellent activity, low toxicity, and no dermal irritation. We hypothesized that DDEAC reacts with air CO2 to form a two-chain ammonium carbamate--Transkarbam 12 (T12)--which is responsible for the enhancing effect.
DDEAC and T12 were synthesized, their structures were confirmed by spectral methods, and their enhancing activity was studied using the Franz diffusion cell and human skin. A high-performance liquid chromatography method was developed for determination of T12, and its biodegradability was evaluated using porcine esterase.
Only the carbamate salt T12 was responsible for the high enhancing activity; DDEAC tested under argon to avoid reaction with CO2 was inactive. T12 enhanced transdermal permeation of drugs covering a wide range of physicochemical properties, including theophylline (enhancement ratio up to 55.6), clotrimazole (7.7), flobufen (5.0), and griseofulvin (24). The activity was pH-dependent, further confirming the importance of the carbamate structure. The metabolization of T12 followed a second-order kinetics with t(1/2) = 31 min.
Our results indicate that T12 is a promising biodegradable permeation enhancer for a wide range of drugs, and the structurally novel group of carbamate enhancers warrants further investigation.

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    • "Then, after reaching enzymatically active nucleated epidermis, its labile bond could be hydrolyzed, thus releasing known non-toxic compounds with much lower irritation potential. This approach to designing permeation enhancers resulted in the identification of highly potent enhancers with favorable properties, such as DDAIP [16], Transkarbam 12 (T12, [23] [24]), tranexamic acid derivatives [25], and dodecyl 6-(dimethylamino)hexanoate (DDAK, [26–28], Fig. 1B). "
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    ABSTRACT: 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.
    Journal of Controlled Release 11/2012; 165(2). DOI:10.1016/j.jconrel.2012.11.003 · 7.71 Impact Factor
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    • "Permeation enhancers DDEAC and T12 were synthesized as described previously [9] [12]. Both model drugs and all other chemicals including HPLC solvents were purchased from Sigma-Aldrich (Schnelldorf, Germany). "
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    ABSTRACT: Transdermal permeation enhancers are compounds that temporarily increase drug flux through the skin by interacting with constituents of the stratum corneum. Transkarbam 12 (T12) is a highly active, broad-spectrum, biodegradable enhancer with low toxicity and low dermal irritation. We show here that T12 acts by a dual mechanism of action. The first part of this activity is associated with its ammonium carbamate polar head as shown by its pH-dependent effects on the permeation of two model drugs. Once this ammonium carbamate penetrates into the stratum corneum intercellular lipids, it rapidly decomposes releasing two molecules of protonated dodecyl 6-aminohexanoate (DDEAC) and carbon dioxide. This was observed by thermogravimetric analysis and infrared spectroscopy. This step of T12 action influences drug permeation through lipidic pathways, not through the aqueous pores (polar pathway) as shown by its effects on various model drugs and electrical impedance. Consequently, protonated DDEAC released in the stratum corneum is also an active enhancer. It broadens the scope of T12 action since it is also able to increase permeation of hydrophilic drugs that prefer the pore pathway. Thus, this dual effect of T12 is likely responsible for its favorable properties, which make it a good candidate for prospective clinical use.
    Journal of Controlled Release 11/2010; 150(2):164-70. DOI:10.1016/j.jconrel.2010.11.017 · 7.71 Impact Factor
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    • "More over, as esterases are present in the human and animal epidermis (Montagna, 1955), the ester linkage offers the possibility of degradation by skin esterases. The similar researches have been done by some other researchers (Vávrová et al., 2005a; Hrabálek et al., 2006) who found the compound could be hydrolyzed into nontoxic metabolites in vitro using porcine esterase. Examination of the effects of these moieties on the action of penetration enhancers, therefore, should give useful information to help with the development of absorption enhancers. "
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    ABSTRACT: To develop more effective compounds as enhancers, O-acylmenthol derivatives which were expected to be enzymatically hydrolyzed into nontoxic metabolites by esterases in the living epidermis were synthesized from l-menthol and pharmaceutical excipient acids (lactic acid, cinnamic acid, salicylic acid and oleic acid) in this study. Their promoting activity on the percutaneous absorption of five model drugs, 5-fluorouracil (5-FU), isosorbide dinitrate (ISDN), lidocaine (LD), ketoprofen (KP), and indomethacin (IM), which were selected based on their lipophilicity represented by log K(O/W), were tested in vitro across full thickness rat skin with each of the evaluated drugs in saturated donor solution. 2-Isopropyl-5-methylcyclohexyl 2-hydroxypanoate (M-LA) provided the highest increase of accumulation of 5-FU (3.74-fold) and LD (4.19-fold) in the receptor phase while 2-isopropyl-5-methylcyclohexyl cinnamate (M-CA) was ineffective for most of the drugs; Both 2-isopropyl-5-methylcyclohexyl 2-hydroxybenzoate (M-SA) and (E)-2-isopropyl-5-methylcyclohexyl octadec-9-enoate (M-OA) had better promoting effects on the drugs with low water-solubility. The four O-acylmenthol enhancers produced parabolic relationship between the lipophilicity (log K(O/W)) of the model drugs (5-FU, ISDN, KP, IM) and their enhancement ratio of the permeation coefficient (ER(P)), indicating that the lipophilicity of the penetrants has significant effect on the permeation results, r = 0.989 (P=0.144) for M-LA, r = 0.965 (P = 0.216) for M-CA, r = 0.786 (P = 0.630) for M-SA, and r = 0.996 (P = 0.088) for M-OA.
    International Journal of Pharmaceutics 04/2008; 352(1-2):92-103. DOI:10.1016/j.ijpharm.2007.10.017 · 3.65 Impact Factor
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