NZ203632A - Pharmaceutical compositions containing certain 5-(3-aminopropylidene)-dibenzocycloheptadiene derivatives and codergocrine - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £03632 203632 Priority Date(s): .

Comptete Specification Filed: <36.5.'/?'.$ Class Publication Date: ....HP. .^f.

P.O. Journal. No: .

SEW ZEALAND PATENTS ACT, i953 *0, ;No.: Date: ;COMPLETE SPECIFICATION ;PHARMACEUTICAL COMPOSITION CONTAINING A DIBENZO-CYCLOHEPTADIENE ANTI-DEPRESSANT AND AN ERGOT ALKALOID ;X/ We, SANDOZ LTD, 35 Lichtstrasse, CH-4002 Basle, Switzerland; a Swiss Body Corporate hereby declare the invention for which X / we pray that a patent may be granted to rox/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - ;- 1 - ;(followed by la) ;2 0363 ;- la - Coaoi 600 6036 ;* ' Pharmaceutical compositions containing a dibenzocycloheptadiene anti-depressant and an ergot alkaloid The present invention relates to pharmaceutical preparations active as anti-depressants as well as to methods of treating depression.

Depression is one of the most common psychiatric disturbances 5 seen by the physician, especially in the elderly patient. The treatment of depression has generally been improved dramatically by the development of tricyclic anti-depressive agents such as the di-benzocycloheptadiene-type anti-depressants. Unfortunately, the therapeutic effect of such agents is often accompanied by 10 troublesome side effects such as anticholinergic, cardiovascular, and central nervous system (CNS) reactions. In the geriatric patient, these side effects are especially problematical, necessitating the use of lower daily doses of the anti-depressant. At lower doses, however, the effect of the drug is often less than that 15 desired.

In accordance with the present invention it has now surprisingly been found that co-administration of a di-benzocycloheptadiene antidepressant with codergocrine is particularly advantageous in the treatment of depression, allowing dosages of the di-benzocyclohep-20 tadiene to be lowered thus reducing occurrence and severity of undesired side-effects.

This is particularly so on co-administration of a compound.of formula I R ^ ^ ¥«§632 wherein R^, R£ and R3 represent independently hydrogen, chloro or bromo, and R4 and R5 represent independently hydrogen, Chalky!, benzyl or C3_gcycl0alkyl or 5 a pharmaceutical^ acceptable acid addition salt thereof with codergocrine in free base or pharmaceutically acceptable acid addition salt form.

Accordingly in one aspect of the invention there is provided a pharmaceutical preparation comprising as active agents a) a compound of formula I or bromo, and and Rj. represent independently hydrogen, C-j.g-alkyl, benzyl or C^gCycloalkyl , 15 or a pharmaceutically acceptable acid addition salt thereof, and b) codergocrine in free base or pharmaceutically acceptable acid addition salt form, wherein the ratio of active agents a) to b) is from substantially 50 : 1 to substantially 3 : 1 parts by weight. 20363 - 3 - j&Zd Q03G The compounds of formula I are known and can be prepared e.g. as described in USP 3,922,305.

A preferred anti-depressant agent of formula I is 5-(3-methyl-aminopropylidene)-10,ll-dihydro-5H-dibenzo[a,d]cycloheptene referred 5 to herein as nortriptyline.

Codergocrine as used herein stands for a mixture comprising dihydroergocryptine (2:1, oi:{J), dihydroergocornine and :dihydroergocristine in the ratio of 1:1 : 1 by weight and may be employed in free base form or in pharmaceutically 10acceptable acid addition salt form. A particularly preferred form is the mesylate known as "codergocrine mesylate" (BAN) or "ergoloid mesylates" (USAN).

The preparation according to the invention may be prepared in conventional manner using conventional diluents, carriers and 15 conventional galenical techniques.

Forms suitable for oral administration are for example tablets, dispersible powders, granules, capsules, syrups and elixirs or for parental administration e.g. solutions such as sterile injectible solutions. Compositions for oral use may contain one or more 20 conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatable preparation. Tablets may contain the active ingredients in admixture with conventional pharmaceutically acceptable excipients, e.g., inert diluents, such as calcium 25 carbonate, sodium carbonate, lactose, and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents, e.g., starch gelatin and acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and talc. The tablets may be uncoated or coated by known techniques to delay disintegration and 3G adsorption in the gastrointestinal tract and thereby provide a 20363 sustained action over a longer period. Similarly, suspensions, syrups and elixirs may contain the active ingredients in admixture v/ith any of the conventional excipients utilized in the preparation of such compositions, e.g., suspending agents such as methyl-5 cellulose, tragacanth and sodium alginate; wetting agents such as lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan monooleate; and preservatives such as ethyl j3-hydroxybenzoate. Capsules may contain the active ingredients alone or admixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate 10 and kaolin. The injectable compositions are formulated as known in the art. These pharmaceutical preparations may contain up to about 90% of the active ingredients in combination with the carrier or adjuvant. Preferably the preparations are put up in unit dosage form particularly in unit dosage form for oral administration. Such 15 forms may contain the active ingredients separately, e.g. in separate layers in a layer or mantle tablet or in split capsules.

A further aspect of the invention concerns a process for the production of a pharmaceutical preparation as stated above which comprises formulating active agent a) with active agent b) as stated 23 above and optionally putting up the preparation in unit dosage form.

In an in-patient study, five patients ranging in age from 26 to 66 years suffering from depression and having a score of 19 to 30 on the Hamilton Depression Scale (A Rating Scale for Depression, M. Hamilton, Nerosurg. Psychiat. 23, 56-62, I960) were given 25 20 milligrams of nortriptyline and 2 milligrams of codergocrine mesylate three times a day for 4 weeks. [This dosage is below the recommended minimum therapeutic dose for nortriplyline of 75 mg/dayj All five patients had a good response and improved significantly on the combination. The Hamilton Depression Scale score for each patient 30 dropped below 8 and the onset of relief from the depression came 203632 much earlier than is normal with the antidepressant alone. Several patients noticed a significant improvement at the end of the first v/eek. The incidence of side effects was very acceptable and their severity was minimal to mild. All five patients in the study felt they 5 were getting effective treatment for their depression. These results were confirmed in a multi-centre trial involving 53 patients whose ages range from 18 to 55 years.

Treatment is characterised by a rapid onset of action, steady continued improvement often leading to complete remission and low 10 incidence and intensity of side effects compared with treatment using anti-depressant alone.

The combined administration according to the invention is thus indicated for the treatment of depression.

The combined administration according to the invention is also 15 indicated for use in the treatment of the symptoms of senile dementia.

• The combined administration according to the invention is thus particularly advantageous for the treatment of elderly people suffering from senile dementia associated with depression.

The co-administration of active agents a) and b) is accordingly 20 indicated in the treatment of depression and senile dementia particularly when associated with each other.

Accordingly depression and senile dementia with depression can be treated in a subject in need of such treatment, by concomitantly administering to said subject an effective amount of an active agent a) and an active agent b) as stated above.

An indicated weight ratio of active agent a) to active agent b) is from substantially 50 : 1 to substantially 3 : .1, preferably 20 : 1 to 5 : 1, especially 12 : 1 to 8 : 1. 203633 For the preferred co-administration of nortriptyline and codergocrine mesylate a suitable ratio is e.g. ca. 10 : 1.

Compounds of formula I alone are normally administered orally in dosages ranging from 30 to 300 milligrams per day. The Maintainance 5 dosage range after remission and for administration according to the invention is from 30 to 150 milligrams per day. In the adolescent and elderly patient, the dosage range may be much lower e.g. between 30 and 75 milligrams per day, the preferred range of the invention. The especially preferred range is 50 to 60 milligrams per day. When 10 the compound of formula I is administered to the patient at the lower ranges in combination with 3 to 9 milligrams per day of codergocrine e.g. as codergocrine mesylate, the response is essentially equivalent to that obtained with the higher doses of anti-depressant. Examples of combined daily dosages are 30 to 150 rng 15 of active agent a) with 3 to 9 mg of active agent b); especially 30 to 75 mg, particularly 50 to 60 mg of nortriptyline v/ith 3 to 9 mg of codergocrine mesylate. A particular combined daily dosage is 60 mg of nortriptyline with 6 mg of codergocrine mesylate.

Conveniently the active agents are administered in sustained 20 release form or alternatively in divided doses 2 to 4 times a day containing e.g. 7.5 to 75 mg of active agent a) and either additionally or as a separate dosage form e.g. 0.5 to 6 mg of active agent b).

Examples are dosage forms containing 10, 20, 25 or 75 mg of active agent a) and those containing additionally or as a separate 25 dosage form e.g. 0.5, 1.0, 1.5, .2 or 6 mg of active agent bj. A particular dosage form contains 20 mg of nortriptyline and 2 mg of codergocrine mesylate.

The following Example is illustrative of compositions for use in the invention. 203632 EXAMPLE 1 T§^l§5§_§D^_^gsules_Suitab]e_for_0ra1_Admini strati on Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in treating e.g. depression at a dose of one tablet or capsule three times 5 a day.

Weight (mg.) Ingredient Tablet Capsule Nortriptyline HCL (=20 mg Base) 22.7 22.7 Ergoloid mesylate 2 2 Tragacanth 10 Lactose 172.8 225.3 Corn Starch 25 - Talcum 15 - Magnesium Stearate "2.5 250 250 Other capsules and tablets as well as e.g. suppositories, dispersible powders, syrups, elixirs, suspensions or solutions may also be made using conventional carriers and diluents for the desired formulation and may be administered enterally or parenterally 20 as apporpriate to a patient. 203633

Claims (9)

WHAT WE CLAIM IS:

1. A pharmaceutical preparation comprising as active agents a) a compound of formula I R, wherein R-j, R? and represent indspendentlv hydrogen, chloro or bromo, and R^ and R^ represent independently hydrogen, galkyl, benzyl or C^gcycloalkyl, or a.pharmaceutically acceptable acid addition salt thereof, and b) codergocrine in free base or pharmaceutical^. acceptable acid addition salt form, wherein the ratio of active agents a) to b) is from substantially 50 : 1 to substantially 3 : 1 parts by weight.

2. A preparation according to Claim 1, wherein active agent a) is nortriptyline or the hydrochloride thereof.

3. A preparation according to Claim 1 or 2 wherein active agent b) is codergocrine mesylate.

4. A preparation according to any one of Claims 1 to 3 wherein the ratio of active agent a) to active agent b) is from 20 : 1 to 5 : 1 parts by weight.

5. A preparation according to Claim 4 wherein the ratio is about 10 : 1.

6. A preparation according to any one of Claims 1 to 5 in unit dosage form. 203632 - 9 -

7. A preparation according to Claim 6 containing 10 to 25 mg of active agent a).

8. A process for the production of a pharmaceutical preparation according to Claim 1 which comprises formulating active agent a) with active agent b) as stated in Clairr< 1. .

9. A composition according to any one of Claims 1 to 7 for use as an anti-depressant and in the treatment of senile dementia with depression. QAlfcU THi:S tOK. CAY Or A. J , y A R K Si 8 O N pc^ AG'HN'i'a :::OR AFPsJOANtfa