AU676672B2 - Brofaromine as an agent for treating post-traumatic stress - Google Patents

Description

OPI DATE 13/09/93 AOJP DATE 25/11/93 APPLN. ID 34844/93 PCT NUMBER PCT/US93/00728 AU9334844 (51) International Patent Classification 5 (Il) International Publication Number: WO 93/16695 A61K 31/445 Al (43) International Publication Date: 2 September 1993 (02.09.93) (21) International Application Number: PCT/US93/00728 (72) Inventor; and Inventor/Applicant (for US onl') KATZ, Richard [US/ (22) International Filing Date: 27 January 1993 (27.01.93) US]; 625 Cumberland Avenue, Teaneck, NJ 07666 (US).

(74) Agent: FISHMAN, Irving, Ciba-Geigy Corporation, Priority data: Patent Department, Rm. F-3173, 556 Morris Avenue, 07/839,639 21 February 1992 (21.02.92) US Summit, NJ 07901 (US).

Parent Application or Grant (81) Designated States: AU, CA, FI, JP, KR, NO, NZ, PL, RU, (63) Related by Continuation UA, US, European patent (AT, BE, CH, DE, DK, ES, US 07/839,639 (CIP) FR, GB, GR, IE, IT, LU, MC, NL, PT, SE).

Filed on 21 February 1992 (21.02.92) Published (71) Applicant (for all designated States except US): CIBA-GEI- With international search report.

GY AG [CH/CH]; Klybeckstrasse 141, CH-4002 Basle

(CH).

676 6 72 (54)Title: BROFAROMINE AS AN AGENT FOR TREATING POST-TRAUMATIC STRESS (57) Abstract Method of treating post-traumatic stress disorder in a warm-blooded animal in need of such treatment comprising administering to said animal a post-traumatic stress disorder treating effective amount of brofaromine or a pharmaceutically acceptable salt thereof.

WO 93/16695 PCT/US93/00728 BROFAROM AS A AGT FOR TRATG POST-TRAUMATC STRSS BROFAROMINE AS AN AGENT FOR TREATING POST-TRAUMATIC STRESS FIELD OF THE INVENTION The present invention relates to psychological disorders associated with traumatic stress and its management. The invention further deals with brofaromine, a selective, reversible monoamine oxidase type A inhibitor, with serotonin uptake inhibitory properties..

BACKGROUND

Brofaromine is an Monoamine Oxidase (MAO) inhibitor antidepressant compound, first patented in the US in 1980 by Schenker et al. (US 4,210,655), which patent is incorporated herein by reference. This patent states that brofaromine, i.e. 4-(5-methoxy-2benzofuranyl)-piperidine, is a selective MAO type A inhibitor, blocks serotonin reuptake, and that the compound is useful in the treatment of depression.

J. Neural Transm (1989) [Suppl] 28: 21-31 discusses the differences in effect on tyramine-elicited blood pressure elevation in subjects which were not medicated, medicated with irreversible MAO inhibitors, or reversible MAO inhibitors. Brofaromine and moclobemide are mentioned specifically as the reversible MAO inhibitors. There is no mention or suggestion of efficacy in psychological disorders of any kind.

J. Neural Transm (1989) [Suppl] 28: 33-44 reports on the therapeutic and side effect profile of brofaromine in the context of depressive disease states.

In recent years, it has become increasingly clear that there are a number of distinct psychological disorders that are not well understood and have been inappropriately WO 93/16695 IICT/US93/00728 -2lumped together in the past. Many of these disorders can occur with or without depression as a component thereof. Separate and apart from depression, the following have now been recognized by DSM-III-R, the diagnostic and statistical manual of the American Psychiatric Association, as distinct disorders: panic disorder with agoraphobia, social phobia, bulimia, borderline personality disorder, and post-traumatic stress disorder (PTSD) among others.

PTSD is a condition believed to be brought on by the witnessing of traumatic events which so shock ones sensibilities that an indelible mark is left on the individual. Motor vehicle accidents, war injuries, crime (especially violent crime), child and spousal abuse, natural disasters, industrial accidents, etc. are typical types of incidents which carry some of the hallmarks of PTSD in susceptible patients whether or not there is any significant physical injury to the victim of or participant in the event. More importantly, there is an even larger population of patients exhibiting the symptoms of the disorder who have merely witnessed the events, especially if the witnessed events are particularly horrifying.

The disorder is characterized by: reexperiencing of intrusive thoughts and images in waking and sleep, increased arousal and hypersensitivity to trauma-related stimulation, and persistent avoidance activity. According to the American Psychiatric Association DSM-Il-R criteria, PTSD is diagnosed when 1. the patient has experienced an event outside the range of usual human experience and that event would be distressing to almost everyone; 2. the patient has recurrent and intrusive distressing recollections or dreams of the event or feelings of the event recurring or psychological distress at exposure; 3. the patient persistently practices at least three avoidant behaviors such as making efforts to avoid thoughts or feelings, making efforts to avoid activities or situations, has psychogenic amnesia of the trauma, has lessened interest in significant activities, is detached or estranged, has a sense of foreshortened future, and a restricted range of affect; 4. the a patient has increased arousal evidenced by at least two of difficulty in falling or staying asleep, irritability or outbursts of anger, difficulty in concentrating, hypervigilence, and exaggerated startle response; and Ac.n the symptoms have persisted for at least one month.

Liebowitz et al, "Reversible and irreversible monoamine oxidase inhibitors in other S~4 psychiatric disorders", Acta Psychiatr Scand 1990: Suppl 260: 29-34, summarize the 1^ W6 93/16695 PCT/US93/00728 -3studies showing that MAO inhibitors generally have some utility in treating these disorders. The authors conclude that the reversible MAO inhibitors, such as moclobemide, appear safer than the classical irreversible MAO inhibitors for these and other therapeutic applications generally ascribed to MAO inhibitors, if they are in fact found to be efficacious for those utilities. With specific reference to PTSD, the authors do not indicate that any reversible or selective MAO inhibitor has been studied. At page 32, Column 1, lines 7-8, the authors state that both the classical MAO inhibitors and the reversible MAO inhibitors need to be studied further in PTSD.

PTSD is a psychological disease state for which various treatments have been reviewed in Arch Gen Psychiatry, Vol 47, March 1990, pp 259-266; J. Clin Psychiatry 51:10 (suppl), pp 33-38, October 1990; and M. Friedman, "Biological Approaches to the Diagnosis and Treatment of Post-Traumatic Stress Disorder, J. Traumatic Stress 67-91, 1991.

The Journal of Clinical Psychiatry article mentions the use of tricyclic antidepressants and MAO inhibitors generally in the treatment of PTSD. These are discussed at page 34, Column 2 through page 35, Column 2. The only MAO inhibitor discussed is phenelzine and the symptoms showing improvement fall into the intrusive recollections and hyperarousal areas. There is no mention of any effect on the avoidant behavior aspects of the condition. The Friedman article mentions that virtually every type of psychotropic agent appears to alleviate DSM-III-R intrusive recollections and hyperarousal, but does not alleviate the avoidant symptoms of the disorder. Brofaromine is not mentioned.

Phenelzine is the only MAO inhibitor discussed and appears to be the only agent of this class tested in PTSD heretofore. The Arch Gen Psychiatry reference appears to be cumulative with the other two articles mentioned here.

In addition, recent reports suggest serotonin uptake inhibitors may benefitintrusive avoidant and hostile aspects of PTSD (Davidson, et al, J. Traumatic Stress 419-425 (1991); Shay, J. Traumatic Stress 97-103 (1992), each dealing with fluoxetine).

From the foregoing, it is clear that no agent to date has provided a suitable treatment for PTSD. The tricyclic antidepressants have only been of moderate success. Classical MAO inhibitors (irreversible inhibitors) have been seen to be more, successful, but there use is severely limited by the pressor effects that could result from dietary and other sources of monoamines and the lack of confidence that patients with PTSD could or would adhere to appropriate self regulation of their monoamine intake. A drug combining MAO inhibitory WO 93/16695 PCT/US93/00728 -4and serotonin uptake inhibitory proprieties might be especially of benefit, and represent synergistic benefits upon more symptoms.

The major problem with the use of classical MAO inhibitors is that they have significant safety profile disadvantages, as noted above. Development of newer and better MAO inhibitors would therefore be likely candidates for testing in conditions for which the MAO inhibitors are known to be useful. With the discovery of the reversible MAO inhibitors moclobemide and brofaromine, this was a potential possibility. However, since the particular mechanism of action of classical MAO inhibitors is intimately :d to the reason for their poor safety profiles, one would not expect to obtain any improvement in the safety profile without a concomitant reduction in efficacy merely by having reversible MAO inhibitors.

Additionally, while the classical MAO inhibitors are nonselective and irreversible inhibitors of both type A and type B MAO, moclobemide and brofaromine are selective, inhibitors of type A MAO. As such, one would expect reduced efficacy as compared to the classical MAO inhibitors since with moclobemide and brofaromine, type B MAO is still available to act in its normal course. Moclobemide also has a potential safety problem similar to the classical MAO inhibitors since its metabolite is an MAO type B inhibitor.

MAO type B is primarily responsible for removing tyramine.

OBJECTS OF THE INVENTION It is therefore an object of the invention to provide a treatment for PTSD which overcomes the defects in the existing armamentum for treating PTSD as well as medicaments for the treatment of PTSD.

It is a further object of the invention to provide a PTSD treatment and/or a medicament for the treatment of which can be administered without close supervision of the patient and thereby allow for greater outpatient treatment possibilities.

Another object of the invention is to provide a PTSD treatment and/or a medicament for the treatment of which will reduce or eliminate the avoidant behavior and hostile symptoms of the disorder.

SUMMARY OF THE INVENTION WO 3/16695 PCT/US93/00728 Surprisingly, these and other objects of the invention are achieved by treating post-traumatic stress disorder in a warm-blooded animal in need of such treatment by administering to said animal a post-traumatic stress disorder treating effective amount of brofaromine or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION The present invention is a method of treating post-traumatic stress disorder in a warm-blooded animal in need of such treatment comprising administering to said animal a post-traumatic stress disorder treating effective amount of brofaromine or a pharmaceutically acceptable salt thereof. Brofaromine and its pharmaceutically acceptable salts are disclosed in US Patent 4,210,655, which is incorporated herein by reference. The cited patent also discloses the synthesis of brofaromine and its pharmaceutically acceptable salts, their uses in depression, their pharmaceutical compositions, antidepressant dosages, and routes of administration. All of this disclosure is applicable to the instant invention.

Especially preferred salts of brofaromine for use in the instant invention include, without limitation, the salts formed from the combination of brofaromine with one of the acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, and embonic acid. Most preferably the salt is the hydrochloride.

Particularly advantageous dosage amounts and regimens (based on free brofaromine) are selected from about 0.1 to about 5.0 mg/kg, more preferably about 0.5 to about 2.0 mg/kg, most preferably about 1.0 to about 1.5 mg/kg, given from 1 to 4 times a day in single or divided doses, more preferably from 1 to 3 times a day, and typically given orally or by intravenous injection twice daily.

Preferred compositions of brofaromine contain 50 or 75 mg of brofaromine per dosage unit intended for mammals of 40 to 70 kg. In addition to brofaromine, the compositions typically contain generally acceptable pharmaceutical carriers, such as lactose, saccharose, sorbitol, and mannitol; starches, such as potato starch, corn starch, and amylopectin; WO 93116695 PCT/US93/00728 -6cellulose derivatives; or gelatin. If desirable, the compositions may also contain a lubricant, such as magnesium stearate, calcium stearate, or polyethylene glycol. Other standard agents used in the manufacture of tablets, capsules, or intravenous solutions may also be present as appropriate.

The invention will be further clarified, but is not limited, by the following Examples, which are presented for exemplification purposes only.

Example 1: An adult individual having suffered acute sexual trauma and satisfies the DSM-III-R criteria for PTSD is given brofaromine hydrochloride (in an amount sufficient to administer 50 mg of free brofaromine) twice daily. The normally present psychological sequelae of the trauma, inclusive of images of the traumatic event, social and situational phobic avoidance and increased arousal to associated stimuli are all significantly reduced.

Example 3: An individual having witnessed military atrocities and sati2fies the DSM-III-R criteria for PTSD is given brofaromine hydrochloride (in an amount sufficient to administer 75 mg of free brofaromine) twice daily. Recollections of the trauma, social avoidance, social and vocational disability, and increased arousal to associated stimuli are all substantially reduced.

Example 3: Tablets, each comprising 50 mg of 4-(7-bromo-5-methoxybenzofuran-2-yl)piperidine or of a salt, for example the hydrochloride, thereof, can be prepared as follows: Composition (10 000 tablets) active ingredient 500.0 g lactose 1000.0 g potato starch 852.0 g gelatin 8.0 g talc 60.0 g magnesium stearate 10.0 g silica (highly disperse) 20.0 g ethanol q.s.

The active ingredient is mixed with the lactose and 792 g of potato starch, and the mixture is moistened with an ethanolic solution of the gelatin and granulated through a sieve. After WO 93/16695 PCT/US93/00728 -7drying, the remaining potato starch, the magnesium stearate, the talc and the silica are mixed in and the mixture is compressed to form tablets which each weigh 295.0 mg and comprise 50.0 mg of active ingredient, and which may, if desired, be provided with dividing notches for finer adjustment of the dose.

Example 4: Film-coated tablets, each comprising 50 mg of 4-(7-bromo-5-methoxybenzofuran-2-yl)piperidine or of a salt, for example the hydrochloride, thereof, can be prepared as follows: Composition (for 1000 film-coated tablets) active ingredient 50.0 g lactose 200.0 g corn starch 120.0 g talc 17.0 g calcium stearate 10.0 g hydroxypropylmethylcellulose 2.36 g shellac 0.64 g water q.s.

methylene chloride q.s.

The active ingredient, the lactose and 90 g of the corn starch are mixed, and the mixture is moistened with a paste, prepared from 30 g of corn starch and water (with heating), and granulated. The granules are dried, and the remaining corn starch, the talc and the calcium stearate are added and mixed with the granules. The mixture is compressed to form tablets (weight: 400 mg), which are coated with a solution of the hydroxypropylmethylcellulose and the shellac in methylene chloride; final weight of each film-coated tablet: 583 mg.

Example 5: Hard gelatin capsules, each containing 500 mg of 4-(7-bromo-5-methoxybenzofuran-2-yl)piperidine or of a salt, for example the hydrochloride, thereof, can be prepared, for example, as follows: Composition (for 1000 capsules) active ingredient 500.0 g lactose 250.0 g WO 93/16695 PCT/US93/00728 -8microcrystalline cellulose 30.0 g sodium lauryl sulfate 2.0 g magnesium stearate 8.0 g The sodium lauryl sulfate is added to the lyophilised active ingredient through a sieve having a mesh size of 0.2 mm. The two components are mixed intimately. Then, first the lactose is added through a sieve having a mesh size of 0.6 mm and then the microcrystalline cellulose through a sieve having a mesh size of 0.9 mm. The mixture is mixed intimately again for 10 minutes. Finally, the magnesium stearate is added through a sieve having a mesh size of 0.8 mm. After further mixing for 3 minutes, hard gelatin capsules of a suitable size are each filled with 790 mg of the resulting formulation.

Example 6: A 5 injection or infusion solution of 4-(7-bromo-5-methoxybenzofuran-2yl)piperidine or of a salt, for example the hydrochloride, thereof can be prepared, for example, as follows: Composition (for 1000 or 400 ampoules) active ingredient 125.0 g sodium chloride 22.5 g phosphate buffer pH 7.4 300.0 g demineralised water ad 2500.0 ml The active ingredient and the sodium chlorde are dissolved in 1000 ml of water and filtered through a microfilter. The buffer solution is added, and the mixture is made up to 2500 ml with water. To prepare unit dose forms, 1.0 or 2.5 ml are introduced into each glass ampoule, which then contains 50 or 125 mg, respectively, of active ingredient.

Claims (10)

1. A method of treating post-traumatic stress disorder in a warm-blooded animal in need of such treatment comprising administering to said animal a post-traumatic stress disorder treating effective amount of brofaromine or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 wherein said warm-blooded animal is a human being.

3. The method of claim 1 wherein said effective amount, based on free brofaromine, is from about 0.1 mg/kg to about 5.0 mg/kg.

4. The method of claim 1 wherein said pharmaceutically acceptable salt of brofaromine the hydrochloride salt.

5. The method of claim 1 wherein said administering is via the oral or intravenous route.

6. The method of claim 1 wherein said brofaromine or pharmaceutically acceptable salt thereof is administered in a composition comprising in addition to said brofaromine or salt thereof, a pharmaceutically acceptable carrier.

7. The method of claim 1 wherein said brofaromine or salt thereof is administered orally in a tablet or capsule.

8. A pharmaceutical composition when used for treating post-traumatic stress disorder, containing a social phobia treating effective amount of brofaromine or a pharmaceutically acceptable salt thereof in admixture to conventional pharmaceutical auxiliarie. INTERNATrIONAL SEARCH REPORT International Application No PCT/US 93/00728 1. CLASSIFICATION OFSUBJECT MATTER (if several classification symabols apply, Indicate :i1)6 Accordln.. to International Patent Classification (IPC) or to both National Classification and IPC Int.Cl. 5 A61K31/445 U. FIELDS SEARCHED Minimum Documentation Searchedl classification Systemt Classification Symbols Int.Cl. 5 LA61K Documentation SeArched other than Minimum Documentation to the Extent Wh~v such Documents are Included In the Fields Searthedl Iii. DOCUMENTS CONSIDERED TO BE: RELEVANT 9 Category o Citation of Document, 11 with indication, where appropriate, of the relevant passages L2 Relevant to Claim No. 1 3 X EUR .NEUROPSYCHOPHARMACOL. 1-10 vol. 1, no. 1, November 1990, pages 21 J.FRITZE ET AL. 'Adrenergic-cholinergic imbalances..' see the whole document X ACTA PSYC'IIATR.SCAND. 1-7 vol. 360, no. SUPP, 1990, pages 29 34 M.R.LIEBOWITZ ET AL. 'Reversible and irreversible monoamine oxidase inhibitors in other psychiatric disorders' cited in the application see the whole document 0Special categories of cited documents :o 0 T' Later document published after the international filing date or priority date and not in conflict with the application but document defining the general state of the art which is not cited to understand the principle or thory underlying the considered to be of particular relevance invention earlier docutment but published on or after the International 'X document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to 'V document which may throw doubts on priority claim(s) or Involve an Inventie step which is cited to establish the publication date of another I' doctument of particular relevance; the claimed Invention citation or otht% special reason (as specified) cannot be considered to involve an inventive step when the 0O document referring to an oral disclosure, use, exhibition or document Is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document published prior to the international filing date but In the art. later than the priority date dlaimed 'A document member of the same patent familly IV. CRTFICATION Date of the Actual Completion of the Internatonal Search Data of Mailing of this Intertational Searh Report 21 MAY 1993

11.0OR 93' International Searching Authority Signature of Authorized Officer EUROPEAN PATENT OFFICE THEUNS H. G. Fami PCT/tSAJZIO (ewcml &WdI (J=-7a LWS) PCT/US 93/00728 Interntional Application No

111. DOCUMENTS CONSIDERED TO BE RELEVANT (CONTINUED FROM THE SECOND SHEET) ~Category Citation of Document, with indication, where appropriate, of the relevant passages Releant to Claim No. X US,A,4 210 655 (SCHENKER ET AL.) 1-10 1 July 1980 cited in the application see the whole document A J.CLIN.PSYCHIATR., SUPPL. 1-7 Vol. 51, October 1990, pages 33-38 44-46 J.MSILVER ET AL. 'new approaches in the pharmacotherapy of posttraumatic stress di sorder' see page A PSYCHOPHA IXtACOLOGY 1-7 vol. 106, no. SUPP, 1992, pages S6 S14 W.HAEFELY 'biochemistry and pharmacology of moclobemide, a prototype RIMA' see page S6 Form PCTIISA2IO (e~rt shod) ljmumsY 1US I' I LUNA I ONAI, S 4 CAI(CU IlIl 1 O)ltR' T PCT/US 93/ 00728 Box I Observations where certain claims were round unsearchable (Continuation of item I of frst sheet) This international search rep rt has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 1. O Claims Nos.: because they relate to subject matter not required to be searched by this Authority, namely; 2. Claims Nos.: because they relate t- parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search car. e carried out, specifically: REMARK: Although claims 1-7 are directed to a method of treatment in the se nse of rule 39.1(4) PCT, the search has been based on the alleged effects of the compound. 3. O Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Box II Observi tions where unity of invention is lacking (Continuation of item 2 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows: 1. As all required addiiuonal search fees were timely paid by the applicant, this i-ternational search report covers all searchable claims. 2. As all searchable claims could be searches without effort justifying an additional fee, this Authority did not invite payment of any additional fee. 3. O As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.: 4 D No required addiuonal search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invenuon first mentioned in the claims; it is covered by claims Nos.: Remark on Protest O The additional search fees were accompanied by the applicant's protesL F No protest accompanied the payment of additional search fees. Form PCT/ISA/210 (continuation of first sheet (July 1992) ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. 9300728 69688 This annex k=st the patent family members relating to the patent documents cited in the above-meniod international search report. The members ame as contaitsed in the European Patent Office EDP file on The European Patent Office is in no way lible for them particulars which ame merely given for the purpose of information. 21/05/93 PAtent documvst Publication fPatent family Publication cited in search report Cmember($) date I I 1 US-A-4210655 01-07-80 CH-A- AT-B- AT-B- AT-B- AT-B- AU-A- BE-A- CA-A- CH-A- CH-A- CH-A- CH-A- CH-A- CH-A- CH-A- CH-A- CH-A- CH-A- CH-A- CH-A- CH-A- C H-A- DE-A, C FR-A, B GB-A- Jp-c- JP-A- JP-B- Jp-c- JP-A- JP-B- LU-A- NL-A- SE-B- U S-A- 592656 336014 340921 340923 343662 6619274 811767 1045139 605924 605926 603635 603636 605927 603637 603638 613961 610898 610588 613962 613450 613451 613452 2408476 2219781 1465581 1232880 49117474 59009557 1317414 58004781 60046115 69510 7402755 410856 4600719 31-10-77 12-04-77 10-01-78 10-01-78 12-06-78 04-09-75 02-09-74 26-12-78 13-10-78 13-10-78 31-08-78 3 1-08-78 13-10-78 31-08-78 31-08-78 31-10-79 15-05-79 30-04-79 31-10-79 28-09-79 28-09-79 28-09-79 12-09-74 27-09-74 23-02-77 26-09-84 09-11-74 03-03-84 15-05-86 11-01-83 14-10-85 09-12-75 04-09-74 12-11-79 15-07-86 AM For more details about this annex eOfficial Journal of the European Patent Office, No. 12/82