PCT
`WORLD INTELLECfUAL PROPERTY ORGANIZATION
`International Bureau
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION 1REATY (PCT)
`wo 95/31194
`
`(51) International Patent Classification 6 :
`A61K 31119, 311195
`
`Al
`
`(11) International Publication Number:
`
`(43) International Publication Date:
`
`23 November 1995 (23.11.95)
`
`(21) International Application Number:
`
`PCI'/US95/06044
`
`(22) International Filing Date:
`
`11 May 1995 (11.05.95)
`
`(81) Designated States: AU, CA, JP, MX, US, European patent
`(AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC,
`NL, PT, SE).
`
`(30) Priority Data:
`08/241,603
`
`11 May 1994 (11.05.94)
`
`Published
`With international search report.
`
`US
`
`SHAPIRO, Howard, K.
`(71)(72) Applicant and Inventor:
`[US/US]; 321 North Narberth Avenue, Narberth, PA 19072
`(US).
`
`(74) Agent: PERRELLA, Donald, J.; Wyatt, Gerber, Burke & Badie,
`6th floor, 99 Park Avenue, New York, NY 10016 (US).
`
`(54) Title: COMPOSIDONS FOR TREATMENT OF CHRONIC INFLAMMATORY DISEASES
`
`(57) Abstract
`
`This invention defines novel compositions which can provide a basis for clinical teatment of several chronic inflammatory diseases,
`said diseases including varieties of arthritis, ileitis, colitis and other inflammatory disorders, as well as trauma resulting from ischemia and
`subsequent reperfusion. Increased lipid peroxidation is a common to the etiology of all of the clinical disorders addressed herein. Such
`increased lipid peroxidation generates carbonyl substances which are cytotoxic and additionally serve to perpetuate and disseminate the
`inflammatory process. This invention involves use of orally administered amine derivatives of benzoic acid as carbonyl trapping agents.
`These primary therapeutic agents act by chemically binding to and sequestering the aldehyde and/or ketone products of lipid peroxidation.
`p-Aminobenzoic acid (or PABA) is an example of the primary agent of the present invention. PABA has a small molecular weight, is
`water soluble, has a primary amine group which should react with carbonyl-containing metabolites under physiological conditions and is
`tolerated by the body in relatively high dosages and for extended periods. The method of the present invention includes administration of a
`composition comprising (1) a therapeutically effective amount of at least one carbonyl sequestering primary therapeutic agent, (2) optionally
`one or more co-agent such as, for example, an anti-oxidant free radical trapping substance, and (3) at least one medicament recognized as
`effective to treat said chronic inflammatory disease, so as to produce an additive or synergistic physiological effect of an anti-inflammatory
`nature .
`
`..
`
`0001
`
`PSG2007
`Catalent Pharma Solutions v. Patheon Softgels
`IPR2018-00422
`
`

`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`AT
`AU
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`cs
`cz
`DE
`DK
`ES
`Fl
`FR
`GA
`
`Austria
`Australia
`Barbados
`Belgium
`BurkinaFaso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cllte d'lvoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`Germany
`Denmark
`Spain
`Finland
`France
`Gabon
`
`GB
`GE
`GN
`GR
`HU
`m
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LI
`LK
`LU
`LV
`MC
`MD
`MG
`ML
`MN
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`
`MR
`MW
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SI
`SK
`SN
`TD
`TG
`TJ
`IT
`UA
`us
`uz
`VN
`
`Mauritania
`Malawi
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Slovenia
`Slovakia
`Senegal
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`United States of America
`Uzbekistan
`VietNam
`
`"'
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`0002
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`

`

`W095/31194
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`PCTIUS95/06044
`
`COMPOSITIONS FOR TREATMENT OF CHRONIC INFLAMMATORY DISEASES
`
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`This
`invention relates to the clinical treatment of
`chronic inflammatory diseases, including chronic gingivitis;
`chronic periodontitis; chronic autoimmune gastritis; ileitis;.
`inflammatory bowel disease, including colitis; interstitial
`cystitis; psoriasis; arthritis; tendinitis; carpel tunnel
`syndrome
`and other cumulative
`trauma disorders;
`lupus
`erythematosus; pneumoconiosis; chronic obstructive pulmonary
`disease; inflammatory myopathies; inflammatory neuropathies,
`including Alzheimer's disease, myasthenia gravis and multiple
`sclerosis; epilepsy; as well as lessening of inflammatory site
`edema, and treatment of post-event ischemia and reperfusion
`symptomology resulting from acute central nervous system
`trauma, stroke, kidney ischemia or myocardial infarction.
`2. Description of Prior Art
`The logic and potential value, even synergistic value, of
`using
`two or more
`therapeutic agents in combination for
`treatment of chronic inflammatory diseases has been recognized
`previously
`(Calhoun and coworkers, 1992; Hirschelmann and
`coworkers, 19 91; Brooks and Schwarzer
`( 19 91) ; Wright and
`coworkers, 1977).
`The present disclosure describes the inventive concept of
`using the therapeutic technology of US Patent Application
`07/906,909 in combination with pharmaceutical agents having
`some medicinal value for treatment of the disease entities
`noted above. The inventive concept embodied in my earlier US
`Patent Application 07/906,909 filed 30 June 1992 is the use of
`compositions consisting of a primary agent which sequesters
`carbonyl products in combination with co-agents that have
`known anti-oxidant properties.
`The primary agents of the
`present invention, such as p-aminobenzoic acid (PABA) , contain
`
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`;.,
`a primary amine group, so as to enable reaction with carbonyl
`groups of disease-related substances.
`No pharmacological
`treatment of comprehensive effectiveness is currently avail(cid:173)
`able for any of the chronic inflammatory disorders discussed
`herein. However, a variety of pharmaceutical agents have been
`described which may offer at least some degree of symptomatic
`relief from the clinical effects of these diseases.
`Clinical use of the drug sulfasalazine (SAZ) represents
`a well documented example of the use of a benzoic acid deriva(cid:173)
`tive as a trapping agent for the hydroxyl radical and other
`free radicals in the treatment of a chronic inflammatory dis(cid:173)
`ease.
`In the colon SAZ undergoes reductive cleavage to liber(cid:173)
`ate 5-aminosalicylic acid (5-amino-2-hydroxybenzoic acid, or
`5-ASA), which is the therapeutically active agent. Ahnfelt(cid:173)
`Ronne and coworkers (1990) presented research findings which
`docoment the use of SAZ for successful treatment of chronic
`inflamatory bowel disease (CIBD), also known as ulcerative
`coli tis.
`SAZ is also recognized for use in treatment of
`ileitis (Budavari and coworkers, 1989, pg. 1412). Ahnfelt(cid:173)
`Ronne (1990) compared their in vivo 5-ASA metabolic products
`to products observed after in vitro hydroxylation of 5-ASA by
`the Fenton reaction and tentatively identified 5-ASA metab(cid:173)
`olites as being hydroxylated derivatives.
`They never at(cid:173)
`tempted to look for evidence of in vivo trapping of carbonyl
`products. Under the brand name Asacol and the generic name
`mesalamine, 5-amino-2-hydroxybenzoic acid in delayed-release
`tablets has also been marketed in the United States for use in
`treatment of CIBD (Dowd and coworkers, 1993, pgs. 1868-1869).
`Dull and coworkers (1987, pg. 2469) used mass spectrometry to
`definitively identify two of the several hydroxylation/oxida(cid:173)
`tive deamination products which result from in vitro incuba(cid:173)
`tion of 5-ASA with activated human mononuclear cells. They
`identified these products as gentisic acid (2, 5-dihydroxy(cid:173)
`benzoic acid) and salicylic acid
`(2 -hydroxybenzoic acid) ,
`while five other 5-ASA metabolic products remained uniden(cid:173)
`tified (pg. 2470).
`Ahnfelt-Ronne and colleagues, Dull and coworkers, and
`earlier investigators never recognized the possibility of
`using a therapeutic agent to scavenge carbonyl products of
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`3
`inflammation. Hence they never recognized the possibility of
`intentionally using a composition consisting of a primary
`agent which sequesters carbonyl products in combination with
`co-agents that have known anti-oxidant properties.
`Further distinctions should be noted between the inven(cid:173)
`tion disclosed in US Patent Application 07/906,909 and previ(cid:173)
`ously recognized clinical use of SAZ. SAZ releases sulfapyri(cid:173)
`dine, a somewhat toxic substance, into the body (Peppercorn,
`1984, pgs. 377-379 and 383), while the invention of US Patent
`Application 07/906,909 does not.
`In addition, use of sulfa(cid:173)
`salazine depends on intestinal bacteria for activation of the
`drug, while the primary agents of the present invention do
`not. Besides use in treatment of CIBD, SAZ has been recog(cid:173)
`nized, at least at the experimental level, for treatment of
`ileitis, radiation bowel disease, scleroderma, dermatitis
`herpetiformis and rheumatoid arthritis (Peppercorn, 1984, pgs.
`380-381) .
`Other examples of amine drugs recognized as having anti(cid:173)
`inflammatory properties include para-substituted N-benzene(cid:173)
`sulfonyl derivatives of anthrilic acid (Borne and coworkers,
`1974), 4-amino benzoic acid anilides (Thiele, 1971; Deutsche
`Gold- und Silber-Scheideanstalt vorm. Roessler, 1972), tinori(cid:173)
`dine (Shimada and Yasuda, 1979) and benzothiazolinone deriva(cid:173)
`tives (Takashima and coworkers, 1972). The chemical struc(cid:173)
`tures of these agents lie beyond those of the primary agents
`of the present invention. They are not presently recognized
`as carbonyl sequestering therapeutic agents. They have not
`been used in multiple ingredient compositions analogous to
`those of the present invention.
`Several drug products containing PABA have been marketed
`for human use in the United States. However, it is believed
`that none have been proposed as effective for the treatments
`claimed herein. Potassium p-aminobenzoate has been marketed
`as Potaba (R)
`in the pure form as an antifibrotic, that is,
`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
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`.:.;
`average doses of 12 gm/day for up to two years, although human
`use of 15 - 20 gm/day is recognized. As an ingredient in
`analgesic tablets, PABA has been marketed for domestic human
`use
`(300 mg/tablet)
`in Pabirin
`(R) buffered tablets (with
`aspirin) , in Pabalate (R) tablets (with sodium salicylate) and
`in Pabalate-SF (R)
`tablets (with potassium salicylate), as
`described in Physicians' Desk Reference (Huff and coworkers,
`1980, pgs. 849, with aspirin and 1430, with salicylates) .
`Five percent PABA in a cream base has also been marketed as a
`sunscreen product
`(Physicians' Desk Reference, Huff and
`coworkers, 1980, pg. 849).
`In its summary on systemic use of potassium p-aminobenzo(cid:173)
`ate the Drug Information for the Health Care Professional text
`(8th ed., 1988, pg. 111) presented the following statement
`regarding recognized pharmacology
`(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 im(cid:173)
`balance of serotonin and monoamine oxidase (MAO) mechan(cid:173)
`isms 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. Arninobenzoate
`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.
`In its summary on systemic use of potassium p-aminobenzo(cid:173)
`ate the Physician's Desk Reference (Dowd and coworkers, 1993,
`pg. 1103) presented the following statement (reproduced herein
`its entirety) :
`INDICATIONS
`Based on a review of this drug by the National Acad(cid:173)
`emy of Sciences-National Research Council and/or other
`information, FDA has classified the indications as
`follows:
`'Possibly' effective: Potassium aminobenzoate is possi-
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`b
`bly effective in the treatment of scleroderma, dermato-
`myositis, morphea, linear scleroderma, pemphigus, and
`Peyronie's disease.
`Final classification of the less-than-effective indi(cid:173)
`cations requires further investigation.
`ADVANTAGES
`POTABA offers a means of treatment of serious and often
`chronic entities involving fibrosis and nonsuppurative
`inflammation.
`PHARMACOLOGY
`P-Aminobenzoate is considered a member of the vitamin
`B complex. Small amounts are found in cereal, eggs,
`milk and meats. Detectable amounts are normally pre(cid:173)
`sent in human blood, spinal fluid, urine, and sweat.
`PABA is a component of several biologically important
`systems, and it participates in a number of funda(cid:173)
`mental biological processes. It has been suggested
`that the antifibrosis action of POTABA is due to its
`mediation of increased oxygen uptake at the tissue
`level. Fibrosis is believed to occur from either too
`much serotonin or too little monoamine oxidase activity
`over a period of time. Monoamine oxidase requires an
`adequate supply of oxygen to function properly. By
`increasing oxygen supply at the tissue level POTABA may
`enhance MAO activity and prevent or bring about re(cid:173)
`gression of fibrosis.
`This inventor sees no relationship of such comments to
`the present invention.
`In particular, the comments noted
`above clearly do not recognize the potential use of PABA and
`derivatives thereof as carbonyl trapping agents, that is, as
`agents which may generally inhibit chronic
`inflammatory
`disorders by virtue of their ability to chemically bind to and
`sequester aldehyde and ketone products of lipid peroxidation
`which result from and contribute to the continuation of
`chronic
`inflammatory disorders.
`In addition, prior art
`information has not anticipated or disclosed the particular
`compositions set forth in the present disclosure. Hence the
`clinical applications of PABA and derivatives thereof claimed
`in the present invention are regarded by the inventor as new
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`and novel.
`Certain amine agents have recognized anti-oxidant proper(cid:173)
`ties. These include N,N'-di-(sec-butyl)-p-phenylenediamine
`(Scott, 1965, pg. 120), aniline
`(Scott, 1965, pg. 125),
`aniline N-substituted agents (Scott, 1965, pg. 125), N,N'(cid:173)
`diphenyl-p-phenylenediamine (Swingle and coworkers, 1985, pg.
`112) and ethoxyquin (Swingle and coworkers, 1985, pg. 112).
`In the present invention focus is placed on primary amine
`agents, as such agents are known to covalently react with
`carbonyl agents to yield Schiff base-type products (Feeney and
`coworkers, 1975, pg. 141). By contrast, N-substitution with
`hydrocarbon functional groups tends to increase amine anti(cid:173)
`oxidant activity (Scott, 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, 1965; pgs. 127, 145 and
`158) .
`The carbonyl trapping property of amines depends on
`their ability to form Schiff base-type addition products.
`Zarafonetis (1953) has reported some success in treatment
`of rheumatoid arthritis by use of potassium p-aminobenzoate in
`combination with acetylsalicylic acid and cortisone.
`In this
`report Zarafonetis also described some success in clinical
`treatment of dermatomyositis and scleroderma by use of potas(cid:173)
`sium p-aminobenzoate alone, and referred to earlier work on
`these disorders and other clinically related syndromes, in(cid:173)
`cluding forms of lupus erythematosus.
`Yet Zarafonetis based his logic for diversifying clinical
`studies on PABA or its potassium salt solely on similarities
`of clinical symptoms, comparisons among clinical syndromes
`which feature some common symptomology (Zarafonetis, 1953,
`pgs. 667-668; Zarafonetis, 1964, pgs. 550 and 560; Priestley
`and Brown, 1979, pg. 161; Zarafonetis and coworkers, 1988, pg.
`194) . Zarafonetis never stated an understanding or recognized
`that PABA has the physiological potential of serving as an
`aldehyde chemical trapping agent (Zarafonetis, 1953, pg. 671).
`Hence, he never recognized its potential to sequester aldehyde
`products resulting from increased lipid peroxidation secondary
`to site-specific inflammation.
`In failing to recognize this
`principle, Zarafonetis failed to recognize the potential full
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`scope of clinical applications of PABA.
`Failing to recognize the potential of synergistic anti(cid:173)
`oxidant co-agents, the procedures of Zarafonetis for treatment
`of scleroderma, rheumatoid arthritis and dermatomyositis re(cid:173)
`lied on use of high PABA dosages (12-18 gm/day; see Zarafone(cid:173)
`tis, 1953, pg. 666).
`In principle, it is the understanding of
`the present
`inventor that the clinical prognosis of any
`disease which features increased lipid peroxidation as part of
`its etiology may be improved by clinical application of the
`inventive concept embodied herein.
`Zarafonetis
`(1953) also referred to an earlier study
`which used a combination of p-aminobenzoic acid and a-toco(cid:173)
`pherol to treat scleroderma. Gougerot and Hewitt
`(1951)
`described the logic of their scleroderma treatment protocol as
`follows:
`This observation is to be added to the file of the
`treatment of sclerodermas. Zarafonetis and his collab(cid:173)
`orators have already published 5 cases of sclerodermas
`improved by para-aminobenzoic acid, and in the same
`therapeutic series Shaffer and his collaborators treated
`a generalized scleroderma with para-aminobenzoic acid
`with improvement. In a study of a completely different
`nature, vitamin E (a-tocopherol) was used by Klemperer,
`etc. and in France by Bazex {Lyon, July 1949). This
`is why we have associated the two therapies because of
`their effect on diseases of collagen.
`As such, they perceived their clinical treatment strategy
`to address the status of collagen, with no discussion of pos-
`sible physiological mechanisms.
`Compared to the invention
`embodied herein, Gougerot and Hewitt: (1) failed to recognize
`that either of their therapeutic agents may interfere with the
`inflammatory cascade,
`(2) failed to recognize that primary
`amine and amine-related derivatives of benzoic acid, as a
`class, may bind to and sequester aldehydes which result from
`the inflammatory process,
`(3) failed to understand that the
`combination of a water soluble aldehyde-trapping primary amine
`agent and a lipophilic anti-oxidant agent may have clinical
`application to the treatment of a broad spectrum of chronic
`inflammatory diseases, and (4) failed to disclose the unique
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`positions of the present invention.
`In 1967 Mel'nikova and Ryzhova presented the results of
`a clinical trial wherein PABA was used to treat post-event
`trauma in experimental myocardial infarction, as studied in
`rabbits and dogs. They reported a coronary vasodilator effect
`of PABA based on their understanding of the drug's antihist(cid:173)
`amine property. They recognized no anti-inflamnmatory proper(cid:173)
`ty of PABA and did not understand their findings within such
`a context.
`Subsequent work by Kurdin (1978) has presented evidence
`of increased lipid peroxidation in the process of myocardial
`infarction. Actually, the association of increased levels of
`reactive oxygen species with ischemic myocardial dysfunction,
`with resulting lipid peroxidation is now well recognized
`(Dowling and coworkers, 1990, pg. 465). Viewing the reports
`of Mel'nikova and Ryzhova, Kurdin, and Dowling and coworkers
`within the context of the present invention, the inventor
`proposes that, to some degree, the beneficial effects of PABA
`in the Mel'nikova and Ryzhova study reflected an anti-inflam(cid:173)
`matory property of PABA unrecognized by the investigators, and
`that such a beneficial effect may be optimized by use of the
`multi-component compositions as defined in the present inven(cid:173)
`tion.
`Seekamp and Ward
`(1993), using a rodent hind limb
`ligature model of ischemia/reperfusion, have presented some
`data which demonstrated the value of anti-oxidant pre-treat(cid:173)
`ment of animals with catalase, superoxide dismutase, dimethyl(cid:173)
`sulfoxide, dimethylthiourea or deferoxamine. As itemized by
`Entman and coworkers (1991) , a variety of therapeutic strat(cid:173)
`egies has been proposed for treatment of ischemia/reperfusion
`trauma, yet none of these proposed strategies include the
`present invention.
`The phenomenon of hypoxia/reperfusion injury is now un(cid:173)
`derstood to be an important aspect of several traumatic dis(cid:173)
`ease states, including coronary infarction,
`ischemic acute
`renal failure and cerebral ischemia (Dowling and coworkers,
`1990, pg. 466). Hence, the present invention has significant
`clinical value in the post-event treatment of ischemia and
`reperfusion injury subsequent to myocardial infarction, acute
`kidney failure, and acute central nervous system trauma and
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`f/
`In light of the common physiological relationship of
`stroke.
`hypoxia/reperfusion conditions
`and chronic
`inflammatory
`diseases, both of which include tissue damage caused by lipid
`peroxidation and subsequent liberation of carbonyl substances,
`hypoxia/reperfusion conditions are considered to be varieties
`of chronic inflammatory diseases within the context of this
`invention. Likewise, as the etiology of Alzheimer's disease
`is believed to have an autoimmune component, and use of drugs
`such as deferoxamine
`(McGeer and Rogers, 1992, pg. 448;
`Halliwell, 1991, pg. 593) and indomethacin (Schnabel, 1993)
`has been previously noted in this regard, this disease also
`will be considered to be a variety of chronic inflammatory
`disease within the context of this invention.
`Broad spectrum clinical use of anti-inflammatory vitamin
`compositions which feature PABA as a primary agent, and the
`methodological reasoning for doing so, has not been previously
`recognized or described prior to submission of US Patent
`Application 07/906,909. p-Aminobenzoic acid is not presently
`recognized as a nonsteroidal anti-inflammatory drug (NSAID) .
`Hence, for example, it is not included in the lists of such
`drugs published in (a) the Merck Index, (Budavari and cowork(cid:173)
`ers, 1989, pgs. THER-15 to THER-16),
`(b) Scientific American
`(Weissmann, 1991, pg. 86),
`(c) Understanding Arthritis
`(Kushner, 1984, pgs. 5.2-53) and (d) the American Journal of
`Medicine (Houston, 1991) . Likewise, PABA is not recognized as
`being a
`11 slow acting 11 anti-inflammatory agent (Understanding
`Arthritis, Kushner, 1984, pgs. 55-57).
`Both PABA and D-penicillamine are primary amine agents
`which also function as anti-oxidant free radical trapping
`agents. Yet as anti-oxidant agents PABA and D-penicillamine
`are presently regarded as being of secondary, nominal value,
`due either to weak anti-oxidant properties or toxic side
`effects, respectively. Thus their use as anti-inflammatory
`agents has been quite limited. Their potential value for
`trapping the aldehyde products of inflammation-related lipid
`peroxidation has never been recognized. Hence the formulation
`of a new composition, such as one having PABA as its primary
`agent, optionally having known anti-oxidant free radical
`scavenging chemicals as co-agents, lacking vitamin C in excess
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`of its RDA and additionally including a recognized medicament
`as defined herein, has never been previously described, and
`the potential for clinical use of such a novel composition in
`treatment of chronic inflammatory diseases has never been
`recognized.
`Further distinctions should be made between the present
`invention and previously recognized use of penicillamine, one
`of the "slow-acting" anti-inflammatory drugs mentioned in
`Understanding Arthritis (Kushner, 1984), a publication of the
`Arthritis Foundation. The primary amine agents described in
`the present invention are all derivatives of aminobenzoic acid
`or aminophenylacetic acid, which should facilitate their safe
`elimination from the body by normal kidney filtration. D(cid:173)
`Penicillamine is not a derivative of aminobenzoic acid or
`aminophenylacetic acid.
`In addition, D-penicillamine has a
`reduced sulfhydryl group, unlike any of the primary agents
`claimed herein.
`The invention embodied herein constitutes an alternative
`slow-acting anti-inflammatory protocol which is believed to be
`inherently safer for the patient and to act via a mechanism
`not previously recognized or described. PABA is not among the
`antimalarial drugs discussed by Kushner (1984, pg. 57), nor is
`it among the antimalarial drugs listed in the Merck Index
`(Budavari and coworkers, 1989, pg. THER-16).
`Many NSAID's are known to commonly induce side effects
`which include gastrointestinal damage,
`liver toxicity and
`kidney toxicity (Brune and Beck, 1991; Kraag, 1985). Most of
`these drugs antagonize the actions of many antihypertensive
`drugs (Houston, 1991) . A variety of less common side effects
`of these drugs have also been reported (O'Brien and Bagby,
`1985) . Use of the present invention in combination with such
`previously recognized medicaments permits the effective use of
`such drugs at lower dosage levels, serves to permit use, in at
`least some cases, of previously known medicaments for more
`extended periods of time and serves to supplement the overall
`clinical benefit to patients. Recognized nonsteroidal anti(cid:173)
`inflammatory drugs include aminoarylcarboxylic acid deriva(cid:173)
`tives, arylacetic acid derivatives, arylbutyric acid deriva(cid:173)
`tives, arylcarboxylic acids, arylpropionic acid derivatives,
`
`0012
`
`

`

`'
`
`W095/31194
`
`PCT/US95/06044
`
`1 .
`·
`h'
`·
`·
`'dd
`/If.
`pyrazo es, pyrazo ones, sa 1cy 1c ac1
`er1vat1ves, t 1az1ne-
`1
`1
`carboxamides, e-acetamidocaproic acid, S-adenosylmethionine,
`amixetrine, bendazac, benzydamine, bucolome, difenpiramide,
`ditazol, emorfazone, guaiazulene, nabumetone, nimesulide,
`orgotein, oxaceprol, perisoxal, pifoxime and proquazone.
`Within the context of the present invention, the following
`additional drugs should also be regarded as nonsteroidal anti(cid:173)
`inflammatory
`drugs:
`phenidone;
`ketoconazole;
`disodium
`azodisalicylate (a dimer of mesalamine) ; diazo sulfanilamide
`ethylene polymer of 5-aminosalicylate; cyclophosphamide; 6-
`(2,4-difluorophenoxy)-5-methylsulfonylamino-1-indanone;
`ditazol; droxicam; azapropazone; etoclofene; prenazone; 7-[3-
`(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-
`propyl-2H-1-benzopyran-2-carboxylicacid;N-acetylcysteine; S(cid:173)
`carboxymethylcysteine; naphthypramide;
`flavonoids such as
`sideritoflavone, cirsiliol, hypolaetin-8-glucoside, hypo(cid:173)
`laetin, oroxindin, quercetagetin-7-glucoside, gossypin, hibi(cid:173)
`folin, gossypetin and leucocyanidol; tepoxalin, sodium 2-[4-
`(2-oxocyclopentylmethyl)phenyl]propionate dihydrate, 1- [ (4-
`chlorophenyl)methyl]-2-methyl-5-(quinolinylmethoxy)-1H-indole-
`3-aceti·c acid, DL-2- (4-hexyloxyphenyl)glycine cetyl ester, DL-
`2-[4-(5.5-dimethylhexyloxy)phenyl]glycine cetyl ester; and 6-
`methoxy-2-naphthylacetic acid. Likewise, within the context
`of the present invention various gastrointestinal anti-inflam(cid:173)
`matory drugs, antimalarial drugs and antiarthritic/antirheuma(cid:173)
`tic drugs as disclosed in the Merck Index, 11th edition (Buda(cid:173)
`vari and coworkers, 1989) are regarded as nonsteroidal anti(cid:173)
`inflammatory drugs.
`Glucocorticoid drugs are well known. A more complete
`listing of specific examples of such drugs, and of the various
`forms in which these therapeutic agents may be administered,
`can be found in various well known reference works such as,
`for example,
`the Merck Index, 11th edition (Budavari and
`coworkers, 1989).
`Henceforth reference to sanguinarine will include refer(cid:173)
`ence to hydrated and salt derivatives thereof, such as for
`example sanguinarine monohydrate, sanguinarine chloride and
`sanguinarine chloride dihydrate. Co-agent use of all forms of
`amino-glycoside, amphenicol, ansamycin, 13-lactam, lincosamide,
`
`0013
`
`

`

`'
`
`W095/31194
`
`PCTIUS95/06044
`
`/J-
`macrolide, polypeptide
`tetracycline anitbiotics are
`and
`claimed within the scope of the present invention, as well as
`use of cycloserine, mupirocin and tuberin. The various forms
`of these antibiotics are known to those skilled in the art and
`information regarding them can be found in various reference
`works, for example, the Merck Index, 11th edition (Budavari
`and coworkers, 1989).
`Information regarding nonsteroidal
`anti-inflammatory drugs recognized for use by local adminis(cid:173)
`tration or oral administration is known to those skilled in
`the art and may be found in reference works such as the Physi(cid:173)
`cians' Desk Reference, 47th edition (Dowd and coworkers, 1993).
`Henceforth reference to prednisone will include reference
`to its pharmaceutically acceptable ester derivatives thereof,
`such as for example prednisone 21-acetate. Henceforth refer(cid:173)
`ence to prednisolone will include reference to its pharmaceu(cid:173)
`tically acceptable ester and salt derivatives thereof, such as
`for example prednisolone 21-diethylaminoacetate, prednisolone
`21-stearoylglycolate,
`prednisolone
`21-tert-butylacetate,
`prednisolone 21-trimethylacetate, prednisolone 21-acetate,
`prednisolone sodium succinate, prednisolone sodium 21-m-sulfo(cid:173)
`benzoate, and prednisolone sodium phosphate.
`Henceforth
`reference to cortisone will include reference to its pharma(cid:173)
`ceutically acceptable ester and salt derivatives thereof, such
`as for example cortisone 21-acetate, 21-P-cyclopentanepropion(cid:173)
`ate cortisone, cortisone phosphate, cortisone monosodium phos(cid:173)
`phate, cortisone disodium phosphate and cortisone phosphate
`dimethyl ester. Henceforth reference to hydrocortisone will
`include reference to its pharmaceutically acceptable ester and
`salt derivatives thereof, such as for example hydrocortisone
`21-acetate, hydrocortisone 21-bendazac, hydrocortisone 17-
`butyrate, hydrocortisone 17-valerate, hydrocortisone tebutate,
`hydrocortisone 21-sodium succinate, hydrocortisone disodium
`phosphate and
`its progenitor, hydrocortisone phosphate.
`Henceforth reference to methylprednisolone will include refer(cid:173)
`ence to its pharmaceutically acceptable ester and salt deriva(cid:173)
`tives thereof, such as for example methylprednisolone 21-acet(cid:173)
`ate, methylprednisolone sodium 21-succinate and methylpredni(cid:173)
`solone disodium 21-phosphate. Henceforth reference to triam(cid:173)
`cinolone will include reference to its pharmaceutically ac-
`
`0014
`
`

`

`•
`
`WO 95/3ll94
`
`PCT/US95/06044
`
`/')
`ceptable ester and ether derivatives thereof, such as for
`example triamcinolone 16a,21-diacetate, triamcinolone aceton(cid:173)
`ide, triamcinolone acetonide 21-acetate, triamcinolone aceton(cid:173)
`ide di-sodium 21-phosphate, triamcinolone acetonide 21-hemi(cid:173)
`succinate, triamcinolone benetonide and triamcinolone'hexace(cid:173)
`tonide. Henceforth reference to betamethasone will include
`reference to its pharmaceutically acceptable ester and salt
`derivatives thereof, such as for example betamethasone 21-
`acetate, betamethasone 21-adamantoate, betamethasone 17-
`benzoate, betamethasone 17,21-dipropionate, betamethasone 17-
`valerate, betamethasone 17,21-divalerate, betamethasone di(cid:173)
`sodium phosphate and betamethasone monosodium phosphate.
`Henceforth reference to d