Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-09-04
2002-08-20
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S858000, C514S860000, C514S864000, C514S880000, C514S881000
Reexamination Certificate
active
06436926
ABSTRACT:
The present invention relates to novel compositions and their use in the treatment of dermatologic disorders. More particularly, the present invention relates to compositions which contain 4,4′-methylenebis(tetrahydro-1,2,4-thiadiazine) 1,1,1′,1′,-tetraoxide, known generically as taurolidine, as an active ingredient and the use of such compositions in the topical treatment of superficial fungal infections.
Superficial infections are caused by fungi that invade dead tissues of the skin or its appendages (stratum corneum, nails, hair). Microsporum, Trichophyton, and Epidermophyton are the genera most commonly involved in superficial infections. Some of these dermatophytes produce mild or no inflammation; in such cases, the organism may persist indefinitely, causing intermittent remissions and exacerbations. In other cases an acute infection may occur upon onset of the infection, typically causing a sudden vesicular and bullous disease of the feet or an inflamed boggy lesion of the scalp (kerion) that is due to a strong immunologic reaction to the fungus; properly treated acute infection is usually followed by remission or cure.
Since clinical differentiation of the related dermatophytes can be difficult, these infections are more conveniently discussed with reference to the sites involved.
Tinea corporis
(ringworm of the body) is usually caused by a Trichophyton. The characteristic pink-to-red papulosquamous annular lesions have raised borders, expand peripherally, and tend to clear centrally.
Tinea pedis
(ringworm of the feet; athlete's foot) is common. Trichophyton mentagrophytes infections begin in the 3
rd
and 4
th
interdigital spaces and later involve the plantar surface of the arch. The toe web lesions often are macerated and have scaling borders; they may be vesicular. Acute flare-ups, with many vesicles and bullae, are common during warm weather. Infected toenails become thickened and distorted.
T. rubrum
produces a scaling and thickening of the soles, often extending just beyond the plantar surface in a “moccasin” distribution. Itching, pain, inflammation, or vesiculation with concomitant itching or pain may be slight or severe.
Tinea pedis
may be complicated by secondary bacterial infection, cellulitis, or lymphangitis, sometimes of a recurrent nature.
Tinea pedis
may be confused with maceration (from hyperhidrosis and occlusive footgear), with contact dermatitis (from sensitivity to various materials in shoes, particularly adhesive cement), with eczema or with psoriasis.
Tinea unguium
(ringworm of the nails), a form of onychomycosis, is usually caused by a Trichophyton species. Toenail involvement is common in long-standing tinea pedis; infections of the fingernails are less common. The nails become thickened and lusterless, and debris accumulates under the free edge. The nail plate becomes separated and the nail may be destroyed. Differentiating a Trichophyton infection from psoriasis is particularly important because chemotherapy is specific and prolonged treatment is required.
Tinea capitis
(ringworm of the scalp) mainly affects children. It is contagious and may become epidemic.
Trichophyton tonsurans
infection has become the common cause in the USA; other Trichophyton species (e.g.,
T. violaceum
) are common in other parts of the world.
T. tonsurans
infection of the scalp is subtle in onset and characteristics. Inflammation is low-grade and persistent; the lesions are neither annular nor sharply marginated, and the hairs do not fluoresce under Wood's light. Affected areas of the scalp show characteristic black dots resulting from broken hairs. The fungus, an endothrix, produces chains of arthrospores that can be seen microscopically within the hair. Trichophyton species may persist in adults.
Microsporum audouinii and
M. canis,
once predominant, are much less common causes of tinea capitis in the USA.
M. audouinii
lesions are small, scaly, semi-bald grayish patches of broken, lusterless hairs. Infection may be limited to a small area or extend and coalesce until the entire scalp is involved, sometimes with ringed patches extending beyond the scalp margin.
M. canis
and
M. gypseum
usually cause a more inflammatory reaction, with shedding of the infected hairs. A raised, inflamed, boggy granuloma (kerion) may also occur; it is followed shortly by healing. Diagnosis of a Microsporum infection is facilitated by examining the scalp under Wood's light; infected hairs may fluoresce a light, bright green. The organism is an ectothrix, producing spores to form a sheath around the hair. The sheath can be seen on microscopy. Culture of the fungus is also important in establishing the diagnosis.
Tinea cruris
(jock itch), far more common in males, may be caused by various dermatophyte or yeast organisms. Typically, a ringed lesion extends from the crural fold over the adjacent upper inner thigh. Both sides may be affected. Scratch dermatitis and lichenification are often seen. Lesions may be complicated by maceration, miliaria, secondary bacterial or candidal infection, and reactions to treatment. Recurrence is common, since fungi may persist indefinitely on the skin or may repeatedly infect susceptible individuals. Flare-ups occur most often during the summer. Tight clothing or obesity tends to favor growth of the organisms. The infection may be confused with contact dermatitis, psoriasis, erythrasma, or candidiasis. The scrotum is often acutely inflamed in candidal intertrigo, whereas in dermatophyte infections scrotal involvement is usually absent or slight.
We have found that taurolidine has a broad spectrum of activity against the fungi that cause superficial fungal infections such as ringworms (
Tinea corpis
and
capitis
), athlete's foot (
Tinea pedis
), nail infections (onychomycosis), and “jock itch” (
Tinea cruris
).
The broad spectrum of activity of taurolidine against the clinically revelant fungi is set forth in Table 1. Where with the exception of Candida albicans (>5 mg/ml) it has been found that the antifungal activity of taurolidine is approximately equivalent to its antibacterial activity (0.3-0.6 mg/ml).
TABLE 1
Sensitivity of Fungi to Taurolidine
Concentration of Taurolin (mg/ml)
MIC
Organisms
5
2.5
1.25
0.625
0.3
Control
(mg/ml)
C. albicans
(Has. A)
+
++
+++
+++
+++
+++
>5
C. albicans
(I)
+
+++
+++
+++
+++
+++
>5
C. albicans
(Jones)
++
+++
+++
+++
+++
+++
>5
C. albicans
(Wilton)
++
+++
+++
+++
+++
+++
>5
Candida spp.
−
−
−
++
+++
+++
1.25
Aspergillus fumigatus
I
−
−
−
−
++
+++
0.625
Aspergillus fumigatus
II
−
−
−
+
++
+++
1.25
Solid
Aspergillus fumigatus
III
−
−
−
−
++
+++
0.625
Medium
Aspergillus niger
−
−
−
+
++
+++
1.25
Trichophyton mentagrophytes
−
−
−
−
−
+++
<0.3
Epidermophyton floccosum
−
−
−
−
−
++
<0.3
Mucor spp. (Lane)
−
−
−
−
++
+++
0.625
Rhizopus spp.
−
−
−
−
++
+++
0.625
Sporotrichum schenkii
−
−
−
±
++
+++
0.625
Cryptococcus neoformans
−
−
−
−
−
++
<0.3
C. albicans
(Has. A)
−
−
++
+++
+++
+++
2.5
C. albicans
(Jones)
−
++
++
++
++
+++
5
Liquid
C. spp.
−
−
−
−
&p
Krass Frederick
MedPointe, Inc.
Olstein Elliot M.
Stauffer Raymond E.
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