Propanamide, 2-hydroxy-N,N-dimethyl-

Dermal absorption

Administrative data

Endpoint:

dermal absorption

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Published literature in international accepted journal

Data source

Reference

Reference Type:

publication

Title:

Percutaneous absorption of ibuprofen and naproxen: Effect of amide enhancers on transport through rat skin

Author:

W.J. Irwin, F.D. Sanderson and A. Li Wan Po

Year:

1990

Bibliographic source:

International Journal of Pharmaceutics, 66 (1990) 243-252

Materials and methods

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Permeation through isolated rat skin was measured for different N,N-dimethylamides that are structurally related to propanamide, 2-hydroxy-N,N-dimethyl. Furthermore, the impact of N,N-dimethylamides on the dermal penetration of ibuprofen and naproxen was measured.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

N,N-dimethyldecan-1-amide

EC Number:

238-405-1

EC Name:

N,N-dimethyldecan-1-amide

Cas Number:

14433-76-2

Molecular formula:

C12H25NO

IUPAC Name:

N,N-dimethyldecanamide

Constituent 2

Reference substance name:

N,N-dimethylhexanamide

EC Number:

227-406-2

EC Name:

N,N-dimethylhexanamide

Cas Number:

5830-30-8

Molecular formula:

C8H17NO

IUPAC Name:

N,N-dimethylhexanamide

Constituent 3

Reference substance name:

N,N-dimethyloctanamide

EC Number:

214-272-5

EC Name:

N,N-dimethyloctanamide

Cas Number:

1118-92-9

Molecular formula:

C10H21NO

IUPAC Name:

N,N-dimethyloctanamide

Constituent 4

Reference substance name:

N,N-dimethyldodecanamide

EC Number:

221-117-5

EC Name:

N,N-dimethyldodecanamide

Cas Number:

3007-53-2

Molecular formula:

C14H29NO

IUPAC Name:

N,N-dimethyldodecanamide

Constituent 5

Reference substance name:

N,N-dimethylmyristamide

EC Number:

221-151-0

EC Name:

N,N-dimethylmyristamide

Cas Number:

3015-65-4

Molecular formula:

C16H33NO

IUPAC Name:

N,N-dimethyltetradecanamide

Constituent 6

Reference substance name:

N,N-dimethylhexadecan-1-amide

EC Number:

223-427-6

EC Name:

N,N-dimethylhexadecan-1-amide

Cas Number:

3886-91-7

Molecular formula:

C18H37NO

IUPAC Name:

N,N-dimethylhexadecanamide

Details on test material:

N, N-Dimethylamides were synthesised from the appropriate acid chloride [propionic (C3), butyric (C4), valeric (C5) caproic (C6),
caprylic (C8), capric (C10)].

Radiolabelling:

no

Results and discussion

Any other information on results incl. tables

In the rat skin model, the highest penetration potential was measured for N,N-dimethyldecanamide (Kp = 9.26 and 10.05 x 10³ cm/h). Smaller as well as bigger molecules had a lower penetration rate (e.g. N,N-dimethylhexanamide: Kp = 1.63 x 10³cm h^-1); N,N-tetradecanamide:

Kp = 3.01 x 10³cm h^-1).

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).

Applicant's summary and conclusion

Conclusions:

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