Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
1999-10-12
2002-09-03
Kulkosky, Peter F. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S457000, C424S464000, C424S468000, C424S439000, C424S442000, C514S458000, C514S055000, C514S057000
Reexamination Certificate
active
06444221
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the clinical treatment of chronic inflammatory disorders. For purposes of this invention, the category of chronic inflammatory disorders includes chronic gingivitis, chronic periodontitis, chronic autoimmune gastritis, ileitis, colitis, interstitial cystitis, arthritis, tendinitis, cumulative trauma disorders, systemic lupus erythematosus, autoimmune vasculitis, asbestosis, silicosis, Lyme disease, inflammatory myopathies, Duchenne muscular dystrophy, epilepsy, inflammatory neuropathies, myasthenia gravis, multiple sclerosis, inflammatory site edema, post-event acute central nervous system trauma, stroke, and myocardial infarction.
2. Description of Prior Art
Numerous prior art publications disclose that vitamin E functions physiologically as a lipid-soluble anti-oxidant free radical trapping agent. Prior art publications describe methionine as a water-soluble agent, an essential amino acid, an anti-oxidant and a free radical trapping agent.
p-Aminobenzoic acid (PABA) is known as a water-soluble B vitamin, and several published studies have presented evidence to the effect that PABA functions, in part, as a weak anti-oxidant and a weak free radical trapping agent (Maksimov, O B and Rebachuk, N M, 1985, Table 2; Pryor, WA et al., 1976, pg. 201).
Insofar as benzoic acid or derivatives thereof have been recognized as anti-oxidants or free radical trapping agents, their mechanism of action is understood to consist of hydroxyl radical trapping by the benzene ring (Grootveld, M and Halliwell, B, 1988; Halliwell, B and Gutteridge, J M, 1985, pp. 105 and 130; Richmond, R et al., 1981; Repine, J E et al., 1979, pg. 1642). This has been explicitly demonstrated for PABA (Nakken, K F, 1964, pp. 446, 448, 454-457; Nakken, K F and Pihl, A, 1966, pp. 21, 22, 24, 25 and 28). Likewise, mannitol is recognized as an anti-oxidant based on its ability to scavenge hydroxyl radicals (Halliwell, B and Gutteridge, J M, 1985, pp. 97 and 105), and a similar mechanism of action is recognized for dimethyl sulfoxide (Halliwell, B and Gutteridge, J M, 1985, pg. 147) and methionine (Del Maestro, R F, 1980, 164-165).
Several drug products containing PABA have been marketed for human use in the United States. Potassium p-aminobenzoate has been marketed as POTABA® in the pure form as an antifibrotic, i.e., skin softening agent (
Drug Information for the Health Care Professional,
8th ed., 1988;, pgs. 111-113). As such it has been recognized for treatment of Peyronie's disease; diffuse systemic sclerosis; morphea and linear scleroderma; and dermatomyositis. For such purposes, POTABA® is taken orally in average doses of 12 grams/day for up to two years, although human use of 15-20 grams/day is recognized. As an ingredient in analgesic tablets, PABA has been marketed for domestic human use (300 mg/tablet) in PABIRIN® buffered tablets (with aspirin), in PABALATE® tablets (with sodium salicylate) and in PABALATE-SF® tablets (with potassium salicylate), as described in
Physicians's Desk Reference
(Huff, B B, 1980, pgs. 849, with aspirin and 1430, with salicylates).
In its summary on systemic use of PABA, the
Drug Information for the Health Care Professional
text (8th ed., 1988, pg. 111) presented the following statement (reproduced herein its entirety):
Mechanism of action: The mechanism by which aminobenzoate potassium exerts its antifibrotic effect is not known. It has been postulated that fibrosis results from an imbalance of serotonin and monoamine oxidase (MAO) mechanisms at the tissue level. Fibrosis is believed to occur when an excessive serotonin effect is sustained over a period of time. This could be the result of too much serotonin or too little MAO activity. Aminobenzoate potassium increases oxygen utilization at the tissue level. It has been suggested that this increased oxygen utilization could enhance the degradation of serotonin by enhancing MAO activity or other activities that decrease the tissue concentration of serotonin.
This inventor sees no relationship of such comments to the present invention, in particular, to the use of amine drugs in the treatment of chronic inflammatory disorders. Hence the clinical applications of compositions containing PABA claimed in this invention are recognized by the inventor as new and novel.
Certain amine agents have recognized anti-oxidant properties. These include N,N′-di-(sec-butyl)-p-phenylenediamine (Scott, G, 1965, pg. 120), aniline and aniline N-substituted agents (Scott, G, 1965, pg. 125). In the present invention, focus is placed on primary amine agents, as such agents are known to covalently react with carbonyl substances to yield Schiff base-type products (Feeney, RE et al., 1975, pg. 141). By contrast, N-substitution with hydrocarbon functional groups tends to increase amine anti-oxidant activity (Scott, G, 1965, pgs. 125 and 148). These are two distinct chemical phenomena. The anti-oxidant property of amines depends on their ability to act as electron donors to alkoxy or alkylperoxy radicals (Scott, G, 1965; pgs. 127, 145 and 158). The carbonyl trapping property of amines depends on their ability to form Schiff base-type addition products.
Vitamin C (ascorbic acid) is widely recognized as a water-soluble anti-oxidant vitamin. However, numerous published studies which have appeared since 1980 document that vitamin C also can act physiologically as a pro-oxidant (Gutteridge and Wilkins, 1982), an agent which stimulates lipid peroxidation (Chojkier et al., 1989, pgs. 16957 and 16961), and that it is a strong protein glycosylating agent (Ortwerth, B and Olesen, P, 1988, pgs. 12, 14, 16, 18 and 20). Thus, for example, in vitro studies have documented the ability of vitamin C to accelerate the process of cataract formation (Slight et al., 1990, pgs. 369-373). In addition, some evidence suggests that ascorbic acid may act as a factor which stimulates certain reactions which are characteristic of inflammatory diseases. For example, the presence of ascorbic acid in the synovial fluid of the arthritic joint may contribute to degradation of hyaluronic acid (Wong, S F et al., 1981; Higson, F K et al., 1988). For the purposes of the present disclosure, the hyaluronic acid present in the synovial fluid of the arthritic joint is defined as an example of the inflammation site structures that may reasonably be expected to be protected by use of the compositions of the present invention.
The use of dimethyl sulfoxide as a primary agent in combination with co-agents such as vitamins C, E, A, B
1
, B
5
, and B
6
, as well as PABA, inositol, selenium, butylated hydroxytoluene, cysteine, thiodipropionates and zinc has been described for clinical treatment of arthritis (Pearson, D and Shaw, S, 1982, pp. 298). Dimethyl sulfoxide is clearly the primary agent of the composition disclosed on page 298 of Pearson and Shaw, as it is mentioned eight times. On line 27 of page 298, Pearson and Shaw disclose the preferred use of dimethyl sulfoxide in combination with anti-oxidant co-agents. Said anti-oxidant co-agents include PABA, which is mentioned only once on line 37. For the purposes of this disclosure, dimethyl sulfoxide is not included in any category of co-agent.
On page 299, Pearson and Shaw mention the singular use of vitamin B
6
in the treatment of arthritis, and on page 300 Pearson and Shaw advise the use of vitamin B
6
in combination with “other antioxidants” such as “vitamins A, E, B-5, C, and B-1, cysteine[,] zinc, selenium, inositol, choline, and PABA.” Numerous other variations on this list of co-agents have been described publicly (e.g., Passwater, R A, 1985).
The disclosure of Pearson and Shaw contains several deficiencies which are resolved by the present invention. For example, they did not recognize the pro-oxidant, the lipid peroxidation stimulating or the protein glycosylating properties of vitamin C. While Pearson and Shaw (1982) refer repeatedly to vitamin C as the primary agent of their many compositions (e.g., pgs. 468-469 and 611-613), it is no
Di Nola-Baron Liliana
Kulkosky Peter F.
LandOfFree
Methods of treating chronic inflammatory diseases using... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods of treating chronic inflammatory diseases using..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods of treating chronic inflammatory diseases using... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2839329