Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-09-14
2003-07-01
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S440000, C514S557000, C514S458000
Reexamination Certificate
active
06586472
ABSTRACT:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
Not Applicable
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates primarily to methods and compositions for the treatment of rosacea. Rosacea is a chronic inflammatory disorder affecting the blood vessels and pilosebaceous units of the face in middle-aged individuals, afflicting as many as 13 million Americans. Patients with rosacea have papules and pustules superimposed on diffuse erythema and telangiectasia (visible blood vessels) over the central portion of the face. Hence, the clinical features are facial redness, swelling, papules, pustules, and telangiectasias. An important component of the patients' history is often easy flushing and blushing of the face, and this is often accentuated when alcohol, caffeine-containing, or hot spicy foods are ingested. Hyperplasia of the sebaceous glands, connective tissue, and vascular bed of the nose sometimes causes rhinophyma, or a large, red, bulbous nose in addition to the other signs. Ocular complications occur in a small but significant number of rosacea patients; these include blepharitis, chalazion, conjunctivitis, and keratinitis. Progressive keratinitis can lead to scarring and blindness.
Rosacea and the eye complications are usually responsive to tetracycline, but the antibiotic must be continued for life (at the lowest dose that suppresses the condition) because rosacea recurs when therapy is interrupted. In addition to the undesirability of the more prevalent use of antibiotics in general, a disadvantage to such treatments are the possible side effects associated with long-term use of oral antibiotics, such as nausea, gastrointestinal upset, phototoxicity, enhanced susceptibility to yeast infection, and interactions with other medications. Oral antibiotics may also lessen the effectiveness of oral contraceptives. High-potency topical corticosteroid preparations may induce or aggravate pre-existing rosacea and should not be used for long periods of time on the face. Instead, topical metronidazole is sometimes prescribed for reducing skin redness and the number of pimples on the face of patients with rosacea. Laser therapy has been used to reduce the telangiectasia and redness in some cases. (See Wilkin J K: Rosacea: Pathophysiology and Treatment.
Archives of Dermatology,
1994, 130 :359-362; this and subsequent references are expressly incorporated herein by reference.) It would be desirable to have alternate treatments for rosacea.
2. Description of Related Art.
Lipoic acid was originally identified as a bacterial growth factor present in the water-soluble fraction of liver and yeast. It was found to be necessary for the oxidative decarboxylation of pyruvic acid by
Streptococcus fecalis
and for the growth of
Tetrahymena gelii
, and replaced acetate for the growth of
Lactobacillus casei
. It has been variously known as acetate replacing factor, protogen A, and pyruvate oxidation factor.
Subsequent research showed that lipoic acid (LA) was a growth factor for many bacteria and protozoa, and it served as a prosthetic group, coenzyme, or substrate in plants, microorganisms, and animal tissues. Elucidation of its structure and function determined that it is a co-factor for aketo-dehydrogenase complexes, typically bound as lipoamide, that participates in acyl transfer reactions. Its reduced form, dihydrolipoic acid (DHLA), is a potent sulfhydryl reductant. In aqueous systems, both LA and DHLA exhibit antioxidant actions (reviewed by Packer, L., et al.,
Free Rad. Biol. Med.,
1995, 19: 227-250 (1995)). LA has been shown to maintain microsomal protein thiols, protect against hemolysis, and protect against neurological disorders. The protective effect of dietary supplementation of LA against ischemia/reperfusion injury in the Langendorff isolated heart model has also been demonstrated. LA has been suggested for treating systemically, or as adjuvant systemic medication for, liver cirrhosis, atheroschlerosis, diabetes, neurodegenerative diseases, heavy metal poisoning, and Chagas disease (ibid.). It has also been used as an antidote to poisonous mushrooms (ibid., particularly Amanita species,
Merck Index,
11th ed., 1989, entry 9255).
Few references suggest the use of lipoic acid in dermatological compositions. In a 1988 Japanese patent publication (JP 63008315), lipoic acid in cosmetics at concentrations of 0.01% to 1%, preferably 0.05% to 0.5%, or in topical “quasi-drugs” at concentrations of 0.1% to 1.5%, preferably 0.5% to 1.0%, were suggested for inhibiting tyrosinase, and thus melanin formation, to whiten skin.
In 1995, Rawlings, et al., disclosed a composition and method for “improving or preventing the appearance of dry, flaky wrinkled, aged, photodamaged skin and treating skin disorders” (U.S. Pat. No. 5,472,698, column 2, lines 51 to 54) using a synergistic combination of serine and/or N-acetyl serine and a thiol, an “S-ester”, and/or a disulfide (id., lines 28 to 33). Lipoic acid was mentioned as encompassed by the latter ingredient (column 3, lines 29 to 30). However, the patent's terminology was confusing. Thiols and S-esters were disclosed as preferable over disulfides (column 4, lines 1 to 4). Though lipoic acid is a disulfide, it's listed as a thiol in the patent (column 3, lines 29 to 30); perhaps what is referred to as “lipoic acid” is, instead, dihydrolipoic acid. This supposition is reinforced by the fact that a Sigma product was employed in some examples (column 7, line 63). Both oxidized lipoic acid and reduced, i.e., dihydrolipoic acid, are available from that chemical company, so DHLA may have been used. Unfortunately, there is more uncertainty about the effects of DHLA when compared to LA (see Packer, et a/., cited above, 231-234). The only illustrations of alternate sulfur-containing ingredients were acylated cysteine derivatives, including glutathione.
More importantly, the focus of the patent was stimulation of sphingolipid synthesis in skin to improve it (see column 1 at lines 21 to 23 and column 2 at lines 12 to 13). The examples reported that assays monitored ceramide production in cultured human keratinocytes and porcine skin. In the studies, lipoic acid had no effect in compositions without serine. On the contrary, in every reported assay, the lipoic acid values were identical to controls; see Tables 2 and 3. And, though increasing concentrations of lipoic in the presence of a constant amount of serine boosted ceramide production at certain levels of serine (Table 7), other thiols worked equally well (Tables 1, 4, 5, 6, 8, and 9). Read as a whole, the reference teaches away from LA as an active ingredient, and suggests DHLA of efficacy only with serine or N-acetyl serine.
A year later, in U.S. Pat. No. 5,569,670 to Weischer, et al., pharmaceutical compositions containing a synergistic combination of &agr;-lipoic acid and/or dihydrolipoic acid with specific enantiomers of these, together with some vitamins, including C and E (column 1, lines 3 to 15), were disclosed as useful, primarily for treating diabetes (see the claims). However, anti-inflammatories (abstract, line 8 and column 2 at line 16) as well as treatments for retroviruses and other pathological conditions were included, with an emphasis on veterinary applications (column 13, lines 42 to 62). In a test model for inflammation (observing rat edema), the R-enantiomer of lipoic acid was superior to lipoic alone or to vitamin E alone (column 3, lines 37 to 40). Suggested administration was oral, parenteral or intravenous (column 7, line 31 to end, et seq.), preferably oral (column 11, line 42), but application to skin and mucous membranes was mentioned (column 12, lines 58 to 60). Antioxidants could be employed in some embodiments (column 16, lines 47 to 55), and the list included ascorbic acid, ascorbyl “palmirate” [sic] and tocopherols. The examples combined lipoic and/or dihydrolipoic acid with tocopherols (Examples 1, 2, 5, and 6) or ascorbic acid (Examples 3, 4, and 7). An ointment was disclosed in Example 6; the others described supp
St. Onge Steward Johnston & Reens LLC
Travers Russell
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