Topicort

Abstract

The physical and chemical compatibility of desoximetasone ointment 0.25% and tacrolimus ointment 0.1%, both widely used to treat atopic dermatitis, were determined. A 1:1 (w/w) mixture of desoximetasone ointment 0.25% (Topicort[R], Taro Pharmaceuticals USA, Inc.) and tacrolimus ointment 0.1% (Protopic[R], Fujisawa Healthcare, Inc.) were prepared and stored under three different temperature/relative humidity conditions: 25[degrees]C/60% RH; 30[degrees]C/60% RH: and 40[degrees]C/75% RH. Unmixed ointments stored under the same temperature and humidity conditions as the mixture served as controls. Samples were evaluated at days 1, 2, 7, 14, and 28 for color, degree of physical separation, and chemical stability via reverse-phase high performance liquid chromatography. Ranges of relative recovery for each active ingredient for all storage conditions ((% Mixture/% Control) x 100) were 89.6-109.3% for tacrolimus and 99.0-103.4% for desoximetasone. No significant difference in physical appearance or chromatographic profile between the mixture and controls was observed. Therefore, we conclude that desoximetasone ointment 0.25% (Topicort[R]) and tacrolimus ointment 0.1% (Protopic[R]) are physically and chemically compatible up to four weeks when mixed in a ratio of 1:1 (w/w).

**********

Desoximetasone 0.25% ointment is a Class II mid-potency topical steroid (1) widely used in the treatment of atopic dermatitis and other steroid-responsive dermatoses, Tacrolimus 0.1% ointment, a non-steroid topical immunomodulator, is also widely used to treat atopic dermatitis. It has been shown that not all topical products are compatible when mixed. Incompatibility may result from the instability of one active pharmaceutical ingredient in the presence of another active pharmaceutical ingredient or its associated vehicle and excipients. Specific examples of compound-compound incompatibility were demonstrated with Dovonex[R] 0.005% ointment when combined with salicylic acid 6% ointment, ammonium lactate 12% lotion, and hydrocortisone-17-valerate 0.2% ointments (2). Examples of compound-vehicle incompatibility were demonstrated with tazarotene 0.05% gel when combined with betamethasone dipropionate 0.05% gel (although compatible with cream, lotion, or ointment) and clobetasol propionate 0.05% gel (although compatible with ointment) (3). Tacrolimus and desoximetasone have complex structures (Figure 1), and it is not readily obvious that one would be stable in the presence of the other. For this reason, and because patients frequently apply multiple topical medicines simultaneously, we sought to determine the physical and chemical compatibility both qualitatively and quantitatively of the combination of tacrolimus 0.1% ointment (Protopic[R], Fujisawa Healthcare, Inc.) and desoximetasone 0.25% ointment (Topicort[R], Taro Pharmaceuticals USA, Inc.).

[FIGURE 1 OMITTED]

Methods

80 g desoximetasone ointment 0.25% (Topicort[R]) and 80 g tacrolimus ointment 0.1% (Protopic[R]) were mixed at room temperature and stored in glass vials (1:1 w/w). The stability of 10 g of the mixture and control (non-mixed) samples was measured at day 1, 2, 7, 14, and 28 under three different temperature/relative humidity (RH) conditions: 25[degrees]C/60% RH: 30[degrees]C/60% RH; and 40[degrees]C/75% RH.

Compatibility was evaluated visually by color and degree of physical separation; potencies of each active ingredient were determined quantitatively by reverse-phase high performance liquid chromatography (4-7). Quantitation was based on authentic drug substance standard for desoximetasone and on Protopic Injection[R] (5 mg/1 mL) for tacrolimus.

Results

No more than slight separation was observed over any time period under any of the three storage conditions. Mixtures remained white, except for a pale yellow appearance at day 28 under all storage conditions of the mixture and desoximetasone control.

For all times and storage conditions, ranges of recovered materials were:

* Tacrolimus Mixture: 70.0-82.3%;

* Tacrolimus Control: 67.9-81.3%;

* Desoximetasone Mixture: 95.2-102.9%:

* Desoximetasone Control: 93.9-103.5%.

The range of relative recovery ((% Mixture/% Control) x 100) for all storage conditions and all time periods was 89.5-109.7% for tacrolimus, and 99.0-103.4% for desoximetasone. This data is presented graphically in Figures 2-4.

[FIGURE 2-4 OMITTED]

Conclusion

There is no significant difference in either physical appearance or chromatographic profile between the mixture of desoximetasone 0.25% ointment and tacrolimus 0.1% ointment and the individual ointments. Protopic[R] ointment 0.1% (Fujisawa) and Topicort[R] ointment 0.25% (Taro) are compatible both physically and chemically for up to 4 weeks when mixed at a ratio of 1:1 (w/w).

Discussion

The physical compatibility of tacrolimus 0.1% ointment and desoximetasone 0.25% ointment allows for their confident simultaneous application. It is hoped that concomitant use of a steroid and tacrolimus might decrease the incidence of itching, burning, and stinging associated with the use of tacrolimus (8), thereby allowing for increased compliance and ultimate steroid sparing. Given the variability of chemical compatibilities, however, it is important to point out that one cannot be certain that tacrolimus would be compatible with other compounds, or even with desoximetasone in a different vehicle or from a different manufacturer.

References:

(1.) Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, Fitzpatrick TB. Fitzpatrick's Dermatology In General Medicine Fifth Edition. 1999, McGraw-Hill. New York, p.2714.

(2.) Patel B, Siskin S, Krazmien R, Lebwohl M. Compatibility of calcipotriene with other topical medications. J Am Acad Dermatol 1998: 38(6): 1010-1.

(3.) Hecker D. Worsley J, Yueh G, Lebwohl M. In vitro compatibility of tazarotene with other topical treatments of psoriasis. J Am Acad Dermatol 2000; 42(6): 1008-11.

(4.) Jacobson PA, Johnson CE. West NJ, and Foster JA. Stability of tacrolimus in an extemporaneously compounded oral liquid, American journal of Health-System Pharmacy 1997: 54(2): 178-180.

(5.) Akashi T, Nefuji T, Yoshida M, and Hosoda J. Quantitative determination of tautomeric FK506 by reversed phase liquid chromatography. J of Pharmaceutical and Biomedical Analysis 1996: 14:339-346.

(6.) Namiki Y, Kirhara N. Koda S, Hane K, and Yasuda T. Tautomeric Phenomenon of a novel potent immunosuppressant (FK506) in solution. 1. Isolation and structure determination of tautomeric compounds. The Journal of Antibiotics 1993; 46(7): 1149-115.

(7.) Nishikawa T. Hasumi H. Suzuki S, Kubo H, and Ohtani H. Kinetic analysis of molecular interconversion of immunosuppressant FK506 by high-performance liquid chromatography. Pharmaceutical Research 1993: 10(12):1785-1789.

(8.) Nghiem P, Pearson G, Langley RG. Tacrolimus and pimecrolimus: From clever prokaryotes to inhibiting calcineurin and treating atopic dermatitis. J Am Acad Dermatol 2002; 46:228-41.

JACOB LEVITT MD (1), TERRY FELDMAN MD (2), ILDIKO RISS MD, AND ON-TAI LEUNG MD (2)

(1) DEPARTMENT OF DERMATOLOGY, MOUNT SINAI MEDICAL CENTER NEW YORK, NEW YORK

(2) TARO RESEARCH INSTITUTE, TARO PHARMACEUTICALS, INC. BRAMPTON, ONTARIO

ADDRESS FOR CORRESPONDENCE:

Jacob Levitt MD

16 Stone Wall Lane

Mamaroneck, NY 10543

Phone: (914) 661-1726

COPYRIGHT 2003 Journal of Drugs in Dermatology
COPYRIGHT 2004 Gale Group