WO1996029076A2

WO1996029076A2 - Treatment of inflammatory bowel disorders with cotinine

Info

Publication number: WO1996029076A2
Application number: PCT/US1996/003000
Authority: WO
Inventors: Robert M. Keenan
Original assignee: Lectec Corporation
Priority date: 1995-03-17
Filing date: 1996-03-06
Publication date: 1996-09-26
Also published as: AU5092696A; WO1996029076A3

Abstract

A therapeutic method is provided to alleviate the symptoms of an inflammatory bowel disorder comprising administering an amount of cotinine or a pharmaceutically acceptable salt thereof to a human in need of such treatment, which amount is effective to reduce or eliminate at least one of the symptoms of the inflammatory bowel disorder.

Description

TREATMENT OF INFLAMMATORY BOWEL DISORDERS WITH COTININE

Background of the Invention

Inflammatory bowel disorders (IBD) encompass a spectrum of overlapping clinical diseases that appear to lack a common etiology. 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.

Current therapies for ulcerative colitis include a combination of sulfonamide and a salicyclate (sulfasalazine), or targeted delivery of mesalamine to sites along the wall of the small and large bowel. 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. Although the symptoms of many patients with ulcerative colitis can be controlled with these therapies, a considerable number of patients do not respond due to refractory symptoms or toxic effects of the drugs.

Based on the observation that 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)).

In a later randomized, double-blind study, Pullan et al. (N. Eng. J. Med.. 330. 81 1 (1994)) treated ulcerative colitis patients with a transdermal nicotine patch for six weeks, gradually increasing the dose over the six week period. During the study, all patients continued receiving their maintenance dose of sulfasalazine. mesalamine, or low-dose glucocorticoid therapy. Pullan et al. reported that 17/35 patients treated with nicotine who completed the study showed complete remission. This remission was evaluated based on a significant improvement in clinical grade, reduction in stool frequency, increased production of intestinal mucus, decreased urgency and decreased pain. Rectal bleeding, stool consistency, and sigmoidoscopy grade were also slightly improved.

While nicotine therapy may be efficacious in some ulcerative colitis patients, nicotine is nonetheless toxic when employed as a pharmacotherapeutic. A significant number (5/40) of patients initially enrolled in the Pullan et al. study who received nicotine therapy withdrew due to nicotine associated side effects. Three of these patients withdrew within the first three days of the study, when relatively low doses of nicotine were being administered, due to the severity of the side effects which they experienced. When nicotine is orally administered it can cause gastrointestinal upset, a complication that only compounds the discomfort and pain of ulcerative colitis patients. Furthermore, nicotine is not recommended for long term use due to its adverse health effects and its addictive nature. Thus, there is a continuing need for a safe and effective therapeutic method to reduce or eliminate the symptoms associated with ulcerative colitis.

Summary of the Invention 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. 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.

DETAILED DESCRIPTION OF THE INVENTION

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:

(I)

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. Bowman et al., in J. Pharmacol, and EXP. Ther.. 135, 306 (1962) report the preparation of (-)-cotinine free base from (-)-nicotine. The preparation and purification of (-)-cotinine fumarate is described by N.L. Benowitz et al., Clin. Pharmacol. Ther.. 34, 604 (1983). Cotinine is the major metabolite of nicotine which accumulates in the body as a result of nicotine exposure and has previously been believed to be pharmacologically inactive. For example, see N.L. Benowitz, "The use of biologic fluid samples in assessing tobacco smoke consumption", in Measurement in the Analysis and Treatment of Smoking Behavior. J. Grabowski et al.. eds.. NIDA Research Monograph No. 48. U.S. DHHS. PHS. ADAMHA (1983). In contrast to nicotine, 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.

Physiological and subjective effects were noted when cotinine was administered to animals. K.I. Yamamoto et al., International J. Neuropharmacol., 4, 359 (1965) reported that intravenous cotinine produced slight increases in EEG activity and behavioral arousal in cats with only a slight decrease in blood pressure. In squirrel monkeys, intramuscular cotinine injections increased rates of responding on fixed interval schedules of reinforcement over a wide range of doses (M.E. Risner et al., J. Pharmacol. and Exp. Ther.. 234. 1 13 (1985); S.R. Goldberg et al., Psvchopharmacology. 97. 295 (1989)). Hutchinson et al. (U.S. Patent No. 3,870,794), without supporting data, disclose that cotinine can be therapeutically administered to treat certain emotional disorders such as to reduce anger, hostility, irritability, frustration, fear, anxiety and nervousness. These findings, taken together, suggest that cotinine is behaviorally active. However, the pharmacologic mechanism of action has yet to be determined. In two recent human studies, the pharmacokinetic profiles of intravenous and orally administered cotinine were examined without emphasis on measuring the subjective and/or physiological changes induced by this compound (N.L. Benowitz et al., Gin. Pharmacol, and Therapeutics. 34 , 604 (1983); P.J. DeSchepper et al., Eur. J. Pharmacol.. 31_., 583 (1987)). Moreover, using an uncontrolled experimental design. Benowitz et al., Clin. Pharm. and Ther.. 36. 604 (1988), found that intravenous cotinine infusion over 60 minutes produced no cardiovascular changes and significant decreases in subjective ratings of desire to smoke, irritability, low energy and anxiety /tension. These changes were comparable to placebo-induced changes found in other experiments with nicotine. Using a rapid infusion of cotinine over 5 minutes, no significant changes in the subjective ratings were observed. Consequently, Benowitz and his colleagues concluded that cotinine lacked significant pharmacologic activity in humans.

The therapeutic administration of cotinine to abstinent smokers to relieve the symptoms of tobacco withdrawal syndrome has been disclosed in published PCT application 93/23045, published November 25. 1993. 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.

Pharmaceutical formulations 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. Pharmaceutical formulations 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. The 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. Alternatively, 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.

For topical administration to the epidermis, 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.

When desired, 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.

Pharmaceutical formulations 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. For administration by inhalation, 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. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount.

Alternatively, for administration by inhalation or insufflation, 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.

Furthermore, effective doses of 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. For intra-nasal administration, 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).

For topical administration to the eye. 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).

The pharmaceutical compositions according to the invention may also contain other adjuvants such as flavorings, colorings, antimicrobial agents, or preservatives.

It will be further appreciated that the amount of cotinine, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. In general, however, 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.

Ideally, the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.5 to about 75 μM, preferably, about 1 to 50 μM, most preferably, about 2 to about 30 μM. 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.

If cotinine is to be administered in pharmacologically-effective amounts by inhalation of thermally-vaporized cotinine, as by smoking, 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). At these loads of treated smoking material, 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.

Therefore, 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. Likewise, 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.

The invention will be further described by reference to the following detailed example.

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.

Patients will be recruited from the practices of the investigators as well as the outpatient clinics of the Johns Hopkins Bayview Medical Center, and the Johns Hopkins Hospital-Meyerhoff Digestive Disease Center. After informed consent has been obtained, patients will be randomized in double-blind fashion to begin with either placebo or cotinine 100 mg orally qd. After six months, each patient will be crossed over to the other treatment arm. During each of the two 6-month periods of the study, the following measures will be obtained at the times indicated. Month 0:

-flexible sigmoidoscopy with mucosal biopsy -symptom assessment (diary)

-history and physical examination unless performed within 3 months -laboratory assessment (CBC, SMA, 20 ESR) unless performed within

3 months -side effects questionnaire Months 1 -5:

-symptoms assessment (diary) -side effects questionnaire

-office visit with brief physical including rectal exam, hemoccult and vital signs -log of medications taken Month 6: -flexible sigmoidoscopy with biopsy

-symptoms assessment (diary) -disease-specific history & physical -repeat labs (CBC, SMA 20, ESR) -side effects questionnaire -log of medications taken

Patients will continue their usual medications throughout the study plus the study medications. If they develop an acute flare of their ulcerative colitis during the course of the study, they will receive whatever treatment their primary gastroenterologist feels is clinically indicated, but will continue the study medication unless the primary gastroenterologist feels that the flare is more severe than the patient's usual and that the presence of an experimental agent may compromise treatment. 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.

After the study, patients will be returned to their usual care.

It will be apparent to one of ordinary skill in the art that many changes and modifications can be made in the invention without departing from the spirit or scope of the appended claims.

Claims

WHAT IS CLAIMED IS:

1. The use of cotinine or a pharmaceutically acceptable salt thereof to prepare a medicament effective to treat an inflammatory bowel disorder in humans.

2. The use of claim 1 wherein the cotinine is (-)-cotinine.

3. The use of claim 2 wherein the cotinine is a salt of (-)-cotinine.

4. The use of claim 1 wherein the cotinine or the pharmaceutically acceptable salt thereof is administered orally.

5. The use of claim 4 wherein medicament is a chewable composition.

6. The use of claim 1 wherein the medicament is a transdermal patch.

7. The method of claim 1 wherein the medicament is adapted to be administered parenterally.

8. The method of claim 7 wherein the medicament is adapted to be administered intraocular ly.

9. The method of claim 8 wherein the medicament is adapted to be administered via an intraocular insert.

10. The method of claim 7 wherein the medicament is adapted to be administered intravenously.

1 1. The method of claim 7 wherein the medicament is adapted administered intranasallv.

12. The method of claim 7 wherein the medicament is adapted to be administered rectally.

13. The method of claim 1 wherein the medicament is adapted to be administered by inhalation.

14. The method of claim 13 wherein the medicament is adapted to be administered by smoking.

15. The method of claim 1 wherein the inflammatory bowel disorder is Crohn's disease.

16. The method of claim 1 wherein the inflammatory bowel disorder is ulcerative colitis.

17. 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.

18. The article of claim 17 wherein the unit dosage form is a tablet or capsule.

19. The article of claim 17 wherein the unit dosage form is a transdermal patch.

20. The article of claim 17 wherein the unit dosage form is a chewable composition.

21. The article of claim 17 wherein the unit dosage form is an intraocular insert.

22. The article of claim 17 wherein the unit dosage form is an aqueous solution of cotinine or a pharmaceutically acceptable salt thereof.

23. The article of claim 17 wherein the unit dosage form is a suppository.

24. The article of claim 17 wherein the unit dosage form is a cigarette or cigar.

25. The article of claim 17 wherein the inflammatory bowel disorder is Crohn's disease.

26. The article of claim 17 wherein the inflammatory bowel disorder is ulcerative colitis.