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Diss Factsheets

Administrative data

dermal absorption
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Published literature in international accepted journal

Data source

Reference Type:
Percutaneous absorption of ibuprofen and naproxen: Effect of amide enhancers on transport through rat skin
W.J. Irwin, F.D. Sanderson and A. Li Wan Po
Bibliographic source:
International Journal of Pharmaceutics, 66 (1990) 243-252

Materials and methods

GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
N, N-Dimethylamides (C3-C10) were synthesised
from the appropriate acid chloride [propionic (C3), butyric (C4), valeric (C5) caproic (C6),
caprylic (C8), capric (C10)]

Administration / exposure

Details on in vitro test system (if applicable):
The percutaneous absorption of ibuprofen and naproxen through rat skin was studied from suspensions containing different dimethyl amides in an in vitro expermiment. Initial experiments were carried out on stripped and separated skin to observed the effect of a removed stratum corneum. Markersubstances (Ibuprofen and naproxen) were determined with HPCL/UV. Flux, Lag time and Kp were determined for different dimethylamides (1% of C8 or C10) in a 50% propylene glycol (PG) solution. Also content of Dimethylamides were analysed. Addtional the partion cofficent of between rat skin and vehicle containing different enhancer was determined.

Results and discussion

Any other information on results incl. tables

The article leads to the following results for ibuprofen (IBU):

The flux of ibuprofen (IBU) is the highest if C8- (136µmol/(cm2h))or C10-dimethylamides (159µmol/(cm2h)) are added. Only the reference N-methylpyrrolidone (NMPo) lead to a higher flux (203µmol/(cm2h)).

The lag time for IBU is not affected by C8 (3.4h) or C10 -dimethylamides (3.3h) but also not by the reference NMPo (3.4h) [ to compare 50% PG (3.1h) and buffer (3.2h)].

Flux ratio was increase to 2.3 and 1.9 fold for C8 and C10 FADMA respectively (calculated against 50% PG).

Solubility of IBU was only increased 9 or 15% by C10 and C8 FADMA, respectively, while the solubility is increased 280% by NMPo.

And to the following for naproxen (NAP):

The flux of NAP is ten times higher if 1% C10 FADMA is added and seven times higher if C8 FADMA is added. For NMPo (10%) only a 2 fold increase could be observed.

The lag time for NAP is not affected by C8 (2.9h) or C10 (3.3h) whereas NMPo decreases the lag time to 4.9h [to compare 50% PG (2.9h) and buffer (3.6h)].

Flux ratio was determined for C8- and C10 -dimethylamide as 7 and 10 fold, respectively.

Solubility of NAP is increased 57% and 30% if C8- or C10 -dimethylamide is added, but NMPo increases the solubility by 324 %.

Determination of the partition coefficients shows an 3.7 fold (dry) and 5.5 fold (dry) increase compared to 50% PG (propylen glycol).

Determination of the enhancer self thru the skin delivers the following result:

           C8 FADMA: 6.44 µmol/(cm2*24h)

           C10 FADMA: 11.17 µmol/(cm2*24h)

Applicant's summary and conclusion

Clear evidence that the C8 and C10 dimethylamides penetrate the skin and capable increasing the drug partition into the skin.
Executive summary:

Abstract (citation):

"n-Alkanoic N,N-dimethylamides were found to act as penetration enhancers for the transport of ibuprofen and naproxen from

suspensions in 50% aqueous propylene glycol vehicles across rat skin. Stripped skin and separated dermis were used to establish

the maximum potential for enhancement and comparisons with established enhancers such as azone and N-methylpyrollidone were

undertaken. Greatest enhancement was observed with naproxen but both drugs demonstrated a bell-shaped dependence on the alkyl

chain length of the enhancer. Maximum effect was observed with N,N-dimethyloctanamide and N,N-dimethyldecanamide. Measurement of the skin-vehicle partition coefficients indicated that the partition of the drug into the skin was also maximal when these enhancers were incorporated into the vehicle. Permeation studies monitoring the flux of enhancer indicated that these compounds also penetrated the skin most effectively. In contrast, the enhancers had little effect on delivery from liquid paraffin vehicles."Irwin, W. J.; Sanderson, F. D.; Po, A. Li Wan

Percutaneous absorption of ibuprofen and naproxen: effect of amide enhancers on transport through rat skin International Journal of Pharmaceutics (1990), 66(1-3), 243-52