WO1996029076A2 - Traitement des affections instestinales inflammatoires par la cotinine - Google Patents

Traitement des affections instestinales inflammatoires par la cotinine Download PDF

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Publication number
WO1996029076A2
WO1996029076A2 PCT/US1996/003000 US9603000W WO9629076A2 WO 1996029076 A2 WO1996029076 A2 WO 1996029076A2 US 9603000 W US9603000 W US 9603000W WO 9629076 A2 WO9629076 A2 WO 9629076A2
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WO
WIPO (PCT)
Prior art keywords
cotinine
medicament
administered
article
inflammatory bowel
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Application number
PCT/US1996/003000
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English (en)
Other versions
WO1996029076A3 (fr
Inventor
Robert M. Keenan
Original Assignee
Lectec Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lectec Corporation filed Critical Lectec Corporation
Priority to AU50926/96A priority Critical patent/AU5092696A/en
Publication of WO1996029076A2 publication Critical patent/WO1996029076A2/fr
Publication of WO1996029076A3 publication Critical patent/WO1996029076A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

Definitions

  • IBD Inflammatory bowel disorders
  • IBD Inflammatory bowel disorders
  • a common characteristic of IBD is chronic inflammation at various sites in the gastrointestinal tract.
  • Illustrative IBD are ulcerative colitis, Crohn's disease, and infectious colitis.
  • Glafasalazine a salicyclate
  • mesalamine mesalamine
  • Sulfasalazine and the newer non-sulfanamide containing aminosalicylates have been found to be effective in treating mild to moderate cases of ulcerative colitis and in preventing relapse in patients whose ulcerative colitis is quiescent.
  • Glucocorticoid therapy is reserved for treating acute episodes of ulcerative colitis.
  • ulcerative colitis is largely a disease of non-smokers or ex-smokers
  • a number of uncontrolled studies showed that nicotine patches, nicotine chewing gum, and smoking appeared to improve the symptoms of ulcerative colitis (Roberts et al., BMJ, 285. 440 (1982); Hickey, Gut, 30, 416 (1989); Lashner et al., Die. Pis. Sci.. 35, 827 (1990); Srivastava et al., Eur. J. Gastroent.. 3, 815 (1991)).
  • the present invention provides a therapeutic method for the treatment of an inflammatory bowel disorder, such as Crohn's disease or ulcerative colitis, comprising administering to a human patient afflicted with the inflammatory bowel disorder an amount of cotinine, or a pharmaceutically acceptable salt thereof, which amount is effective to reduce or eliminate at least one of the symptoms associated with the inflammatory bowel disorder.
  • a inflammatory bowel disorder such as Crohn's disease or ulcerative colitis
  • cotinine or a pharmaceutically acceptable salt thereof, which amount is effective to reduce or eliminate at least one of the symptoms associated with the inflammatory bowel disorder.
  • These symptoms include, but are not limited to, multiple bowel movements per day, blood or mucus accompanying the bowel movement, urgency, pain, rectal bleeding, and inconsistent stool consistency.
  • Cotinine can be administered by any route including, but not limited to, oral, transdermal, intravenous, inhalation, intraocular, rectal, or intranasal administration.
  • Another embodiment of the present invention is an article of manufacture comprising packaging material and a unit dosage form of a pharmaceutical agent contained within said packaging material, wherein said pharmaceutical agent comprises cotinine or a pharmaceutically acceptable salt thereof in an amount effective to alleviate the symptoms of an inflammatory bowel disorder and wherein said packaging material includes instruction means which indicate that said cotinine or said pharmaceutically acceptable salt thereof can be used for alleviating at least one of the symptoms of the inflammatory bowel disorder.
  • the unit dosage may be in the form of a tablet or capsule, transdermal patch, chewing gum, an intraocular insert, suppository, or an aqueous solution.
  • the packaging material can contain an instruction means such as a label or tag attached to said packaging, a printed package insert, or a prerecorded audio cassette or video tape.
  • cotinine Unlike nicotine, cotinine has a long in vivo half-life, complete oral bioavailability, minimal cardiovascular effect, low potential for abuse and has not been reported to be harmful even at very high doses in many species including man. Cotinine
  • Cotinine (l-methyl-5-(3-pyridinyl)-2-pyrrolidinone) has formula (I) shown below:
  • the physiologically active form is the (-)isomer, so as used herein, the term "cotinine” includes (-)-cotinine, or the racemic form, ( ⁇ )-cotinine.
  • the free base depicted above, can be employed in the practice of the invention, as can the pharmaceutically acceptable salts. These include the amine-acid addition salts of nontoxic organic acids or inorganic acids, such as the tartarate, fumarate ("scotine"), citrate, maleate, malate, hydrobromide, hydrochloride, sulfate, phosphate and the like. For example, see F. Vaitekunas, J. Amer. Che . Soc. 79, 149 (1957). E.R.
  • cotinine has a relatively long terminal elimination half-life (two versus sixteen hours, respectively). Due to this pharmacological characteristic, cotinine has become the principally used objective biochemical marker of nicotine exposure in cigarette smoking and/or cessation-related research paradigms.
  • Cotinine can also be administered by inhalation; in the form of an aerosol either nasally or using delivery vehicles of the type set forth in U.S. Patent No. 4,922,901 to Brooks et al. and U.S. Patent No. 5,099,861 to Clearman et al. or transdermally (e.g., using a transdermal patch).
  • Administration and Dosages While it is possible that, for use in therapy, a compound of the invention may be administered as the pure base, it is preferable to present the active ingredient as a pharmaceutical formulation.
  • the invention thus further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically acceptable carriers and, optionally, other therapeutic and/or prophylactic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • the formulations may, where appropriate, be conveniently presented in discrete unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • compositions suitable for oral administration may conveniently be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution, a suspension or as an emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants. or wetting agents.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives.
  • Cotinine and its derivatives may also be formulated for parenteral administration (e.g., by injection, for example, bolus injection or continuous intravenous or enteral infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • the cotinine may be formulated as ointments, creams, or lotions, or as the active ingredient of a transdermal patch.
  • Suitable transdermal delivery systems are disclosed, for example, in A. Fisher et al. (U.S. Patent No. 4,788,603), or R. Bawa et al. (U.S. Patent Nos. 4,931.279, 4,668,506 and 4,713,224).
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • the active ingredient can also be delivered via iontophoresis, e.g., as disclosed in U.S. Patent Nos. 4,140,122, 4,383,529, or 4,051.842.
  • Formulations suitable for topical administration in the mouth include unit dosage forms such as chewing gums, smokeless tobacco substitutes, lozenges comprising an active ingredient in a flavored base, usually sucrose and an acadia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; mucoadherent gels, and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • the above-described formulations can be adapted to give sustained release of the active ingredient employed, e.g., by combination with certain hydrophilic polymer matrices, e.g., comprising natural gels, synthetic polymer gels or mixtures thereof.
  • compositions suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories.
  • Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or sprays containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
  • the compounds according to the invention are conveniently delivered from an insufflator, nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane. carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds according to the invention may take the form of a dry powder composition, for example, a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form in, for example, capsules or cartridges or, e.g., gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • cotinine can be administered via reduced- or nicotine-free smoking materials.
  • Such materials comprise vegetable material which has been treated with cotinine or a salt thereof, and then formed into cigarettes, cigars or is smokable as pipe tobacco.
  • the compounds of the invention may be administered via a liquid spray, such as via a plastic bottle atomizer. Typical of these are the Mistometer® (Wintrop) and the Medihaler® (Riker).
  • the cotinine can be administered as drops, gels (see, S. Chrai et al., U.S. Patent No. 4,255,415), gums (see S.-L. Lin et al., U.S. Patent No. 4,136,177) or via a prolonged- release ocular insert (see A.S. Michaels, U.S. Patent No. 3,867,519 and H.M. Haddad et al., U.S. Patent No. 3,870,791).
  • compositions according to the invention may also contain other adjuvants such as flavorings, colorings, antimicrobial agents, or preservatives.
  • a suitable dose will be in the range of from about 1 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day, calculated as (-)-cotinine in the free base form.
  • the compound is conveniently administered in unit dosage form; for example, containing 5 to 1000 mg. conveniently 10 to 750 mg. most conveniently, 50 to 500 mg of active ingredient per unit dosage form.
  • the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.5 to about 75 ⁇ M, preferably, about 1 to 50 ⁇ M, most preferably, about 2 to about 30 ⁇ M. This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1-100 mg of the active ingredient. Desirable blood levels may be maintained by continuous infusion to provide about 0.01-5.0 mg/kg/hr or by intermittent infusions containing about 0.4-15 mg/kg of the active ingredient(s).
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two. three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • cotinine or the cotinine salt can be provided to the extent of about 5-50 mg of cotinine or cotinine salt per gram of smoking materials (0.5-5 wt-% of cotinine).
  • the smoking material is then smoked in a pipe by the user (about 5-20 g treated smoking material), or is formed into cigarettes (about 0.75-1.25 g), or cigars (about 5-20 g).
  • the smoker would self-administer about 1 -20 mg cotinine per gram of smoking material which is consumed. For example, a smoker who smokes 20 cigarettes per day would ingest about 100 mg-1.0 g of cotinine, resulting in an actual bioavailable dose of about 20-400 mg of cotinine.
  • a cotinine-treated cigarette, cigar, unit of smoking material and the like can be considered a pharmaceutical unit dosage form, effective to deliver a preselected amount of cotinine to the user.
  • a pack of cotinine-treated cigarettes, a box or package of cotinine-treated cigars, a tin or soft pack of tobacco treated with cotinine, and the like are "kits" as broadly defined herein, insofar as they also comprise instruction means related to the self-administration of cotinine therefrom in accord with the present method.
  • Example I Patients with chronic ulcerative colitis who are currently not experiencing an acute attack will be recruited for a one-year, placebo- controlled trial of cotinine with crossover at six months.
  • Inclusion criteria for the study are ( 1 ) persons between the ages of 18-70, (2) diagnosis of idiopathic ulcerative colitis for at least six months, (3) tissue diagnosis of disease, (4) stable disease activity at time of entry, and (5) adequate birth control if the patient is a female of childbearing capacity.
  • Exclusion criteria are (1 ) known or suspected Crohn's disease, (2) use of steroids or other immunosuppressives at the time of entry (prednisone, azathioprine. or 6-MP), (3) heart rate > 120 ⁇ 50; systolic blood pressure (SBP) > 170 ⁇ 90, and diastolic blood pressure (DBP) > 1 10 ⁇ 50, (4) illicit or legal drug dependence (including cigarettes) or a dependence of less than 2 years prior to beginning the study, (5) current flare of ulcerative colitis or flare in the past 30 days, (6) inability to give informed consent, (7) participation in another drug study less than 30 days prior to entry, or (8) previous segmental or total colectomy.
  • SBP systolic blood pressure
  • DBP diastolic blood pressure
  • Study medication will also be discontinued if symptomatic hypotension, new onset hypertension with SBP > 170 or DBP > 110. chest pain with EKG changes or seizures develop.
  • Data will be analyzed by comparing cotinine and placebo periods for the primary outcome measure of mean disease activity index (calculated from symptom scores).
  • Other dependent variables will be: time in days to first relapse, histological activity score, side effects profile.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un procédé thérapeutique qui permet de traiter les symptomes des affections intestinales inflammatoires par administration de la cotinine ou bien un sel pharmaceutiquement acceptable de ladite cotinine à un patient ayant besoin du traitement considéré. La posologie décrite permet d'éliminer efficacement au moins l'un des symptomes dans les affections intestinales inflammatoires.
PCT/US1996/003000 1995-03-17 1996-03-06 Traitement des affections instestinales inflammatoires par la cotinine WO1996029076A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU50926/96A AU5092696A (en) 1995-03-17 1996-03-06 Treatment of inflammatory bowel disorders with cotinine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US40560795A 1995-03-17 1995-03-17
US08/405,607 1995-03-17

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WO1996029076A2 true WO1996029076A2 (fr) 1996-09-26
WO1996029076A3 WO1996029076A3 (fr) 1997-02-13

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997034605A1 (fr) * 1996-03-21 1997-09-25 Mayo Foundation For Medical Education And Research Utilisation de nicotine pour traiter une hepatopathie

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023045A1 (fr) * 1992-05-18 1993-11-25 Pharmaco Behavioral Associates, Inc. Utilisation de la cotinine pour calmer le syndrome de sevrage du tabac

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023045A1 (fr) * 1992-05-18 1993-11-25 Pharmaco Behavioral Associates, Inc. Utilisation de la cotinine pour calmer le syndrome de sevrage du tabac

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
94TH ANNUAL MEETING OF THE AMERICAN GASTROENTEROLOGICAL ASSOCIATION, BOSTON, MASSACHUSETTS, USA, MAY 15-21, 1993. GASTROENTEROLOGY, 104 (4 SUPPL.). 1993. A527., XP000600394 JAMESON J S ET AL: "THE EFFECT OF SMOKING ON COLONIC PRESSURE ACTIVITY" *
EUROPEAN JOURNAL OF PHARMACOLOGY, 1995, 278/1 (R11-R12), NETHERLANDS, XP000600463 VAN DIJK J.P.M. ET AL: "Nicotine inhibits cytokine synthesis by mouse colonic mucosa" *
HUM TOXICOL, NOV 1989, 8 (6) P461-3, ENGLAND, XP000600409 SRIVASTAVA ED ET AL: "Effect of nicotine and cotinine on the production of oxygen free radicals by neutrophils in smokers and non-smokers." *
N ENGL J MED, MAR 24 1994, 330 (12) P811-5, UNITED STATES, XP000600452 PULLAN RD ET AL: "Transdermal nicotine for active ulcerative colitis" cited in the application *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997034605A1 (fr) * 1996-03-21 1997-09-25 Mayo Foundation For Medical Education And Research Utilisation de nicotine pour traiter une hepatopathie

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Publication number Publication date
WO1996029076A3 (fr) 1997-02-13
AU5092696A (en) 1996-10-08

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