Correspondence
737
SIR, Recently, Ayres & Hooper (1978) reported on the assessment of the skin penetration properties of topically applied hydrocortisone in different carrier vehicles. The rationale for the work was clearly to obtain comparisons between the different carrier vehicles used in the four different proprietary preparations examined. The hydrocortisone (^H) was not added alone to the base but was added to rhe preparation already containing unlabelled hydrocortisone. This could only be considered permissible if the delivery of the hydrocortisone (^H) to the skin is unaffected by the presence of the original unlabelled hydrocortisone and the addition of the hydrocortisone (^H) to the manufactured preparation does not unintentionally alter its efficacy. It is reasonable to assume that the availability for absorption of the hydrocortisone in the original preparation will affect the absorption of hydrocortisone (^H). The ratio of the amount of hydrocortisone (^H) to the amount of unlabelled hydrocortisone delivered to the skin will be unique for each preparation and will be dependent upon a combination of the physico-chemical nature of the individual carrier vehicle, and the physical forms of both the unlabelled and labelled hydrocortisone in the base. These aspects appear to have been ignored by the authors in the experimental design and their interpretation of the results contradict the in vivo 'bio-availabilities' foimd by Barry & Woodford (1976) to the extent that even the rank order is different. Whereas the unlabelled hydrocortisone is incorporated into the Calmurid HC and Efcortelan bases as suspended crystals of controlled particle size, the technique described for the incorporation of hydrocortisone (^H) will result in crystals of uncontrolled particle size. In Topisone the unlabelled hydrocortisone is predominantly in solution in propylene glycol and it is expected that the hydrocortisone (^H) will also go into solution in the propylene glycol although it is possible that this may be limited by saturation. The addition of hydrocortisone (^H) to the Alphaderm probably results in dissolution into an unsaturated solution of hydrocortisone in the lipid phase. The proportion of hydrocortisone (^H) used as tracer was 4 parts/100 million parts of carrier vehicle. For dilution of this magnitude to be successful the dispersion needs to be thorough and exhaustively evaluated at a scale of scrutiny relevant to the subsequent use of the preparation. The area of skin over which radioactivity was assessed was approximately 100 mm^ and the effective thickness of the film of carrier vehicle involved in delivery of the hydrocortisone to the skin can be expected to be in the range 10-100 ixm, and hence the preparation should be checked for imiformity of hydrocortisone (^H) at a scale of scrutiny somewhere in the range i-io mg. Whilst the degree of variation of hydrocortisone (^H) between the products was evaluated the degree of variation between samples of the same product was not quoted. School of Pharmacy, Sunderland Polytechnic, Galen Building, Green Terrace, Sunderland SRi 3SD
N.A.ORR J.F.SMITH E.A.HILL
REFERENCES
AYRES, P.J.W. & HOOPER, G . (1978) Assessment of the skin penetration properties of different carrier vehicles for topical applied cortisone. British Journal of Dermatology, 99, 307. BARRY, B.W. & WOODFORD, R. (1976) Proprietary hydrocortisone creams: vasoconstrictor activities and bioavailabilities of six preparations. British Journal of Dermatology, 95, 423.
SIR, Thank you for giving us the opportunity to assess the comments in the letters by Whitefield, and by Orr, Smith & Hill. Their comments can be answered under two headings, first those referring to the distribution of the hydrocortisone in the creams and its diffusion from them, and secondly those referring to bio-availability. We agree with Orr et al. that ^H-cortisol is affected by the presence of the unlabelled cortisol, but
737
SIR, Recently, Ayres & Hooper (1978) reported on the assessment of the skin penetration properties of topically applied hydrocortisone in different carrier vehicles. The rationale for the work was clearly to obtain comparisons between the different carrier vehicles used in the four different proprietary preparations examined. The hydrocortisone (^H) was not added alone to the base but was added to rhe preparation already containing unlabelled hydrocortisone. This could only be considered permissible if the delivery of the hydrocortisone (^H) to the skin is unaffected by the presence of the original unlabelled hydrocortisone and the addition of the hydrocortisone (^H) to the manufactured preparation does not unintentionally alter its efficacy. It is reasonable to assume that the availability for absorption of the hydrocortisone in the original preparation will affect the absorption of hydrocortisone (^H). The ratio of the amount of hydrocortisone (^H) to the amount of unlabelled hydrocortisone delivered to the skin will be unique for each preparation and will be dependent upon a combination of the physico-chemical nature of the individual carrier vehicle, and the physical forms of both the unlabelled and labelled hydrocortisone in the base. These aspects appear to have been ignored by the authors in the experimental design and their interpretation of the results contradict the in vivo 'bio-availabilities' foimd by Barry & Woodford (1976) to the extent that even the rank order is different. Whereas the unlabelled hydrocortisone is incorporated into the Calmurid HC and Efcortelan bases as suspended crystals of controlled particle size, the technique described for the incorporation of hydrocortisone (^H) will result in crystals of uncontrolled particle size. In Topisone the unlabelled hydrocortisone is predominantly in solution in propylene glycol and it is expected that the hydrocortisone (^H) will also go into solution in the propylene glycol although it is possible that this may be limited by saturation. The addition of hydrocortisone (^H) to the Alphaderm probably results in dissolution into an unsaturated solution of hydrocortisone in the lipid phase. The proportion of hydrocortisone (^H) used as tracer was 4 parts/100 million parts of carrier vehicle. For dilution of this magnitude to be successful the dispersion needs to be thorough and exhaustively evaluated at a scale of scrutiny relevant to the subsequent use of the preparation. The area of skin over which radioactivity was assessed was approximately 100 mm^ and the effective thickness of the film of carrier vehicle involved in delivery of the hydrocortisone to the skin can be expected to be in the range 10-100 ixm, and hence the preparation should be checked for imiformity of hydrocortisone (^H) at a scale of scrutiny somewhere in the range i-io mg. Whilst the degree of variation of hydrocortisone (^H) between the products was evaluated the degree of variation between samples of the same product was not quoted. School of Pharmacy, Sunderland Polytechnic, Galen Building, Green Terrace, Sunderland SRi 3SD
N.A.ORR J.F.SMITH E.A.HILL
REFERENCES
AYRES, P.J.W. & HOOPER, G . (1978) Assessment of the skin penetration properties of different carrier vehicles for topical applied cortisone. British Journal of Dermatology, 99, 307. BARRY, B.W. & WOODFORD, R. (1976) Proprietary hydrocortisone creams: vasoconstrictor activities and bioavailabilities of six preparations. British Journal of Dermatology, 95, 423.
SIR, Thank you for giving us the opportunity to assess the comments in the letters by Whitefield, and by Orr, Smith & Hill. Their comments can be answered under two headings, first those referring to the distribution of the hydrocortisone in the creams and its diffusion from them, and secondly those referring to bio-availability. We agree with Orr et al. that ^H-cortisol is affected by the presence of the unlabelled cortisol, but
