GB2173699A - Pharmaceutical compositions with antilactational activity - Google Patents

Abstract

Hydrogenated ergot alkaloids, specifically dihydroergocristine and/or dihydroergocryptine and/or their pharmaceutically acceptable salts, are used to manufacture medicaments for use in treating puerperal galactorrhea. The compositions, which are for internal use (e.g. as tablets or injections) may also contain dihydroergocornine.

Description

SPECIFICATION Pharmaceutical compositions with antigalactopoietic activity The present invention concerns pharmaceutical compositions for the treatment of puerperal galactorrhea as well as a therapeutical method covering the administration of said compositions in patients suffering from said condition.

In medical practice, it is largely known the use of ergolinic derivatives, and particularly bromocriptine and metergoline in the same indication: in this case, the activity of presently available drugs is related to a reduction of prolactinaemia induced by stimulating dopaminergic D2 hypophyseal receptors (L. Varga et al., Br. Med. J., 1972,2,743; P. G. Crosignani et al., Obstet. Gynec., 1978,51, 113).

Now it has been found that hydrogenated ergot alkaloids can be conveniently used as inhibitors of puerperal lactation, with an activity higher than the one of bromocriptine and metergoline. To the end of this invention the alkaloids dihydroergocristine or o-dihydroergocryptine in the form of free bases or salts with pharmaceutically acceptable acids (mesylates, p-toluene-sulfonates, etc.) are particularly preferred.

Dihydroergocristine and a-dihydroergocryptine, alone or associated with dihydroergocornine, are compounds already used in human therapy for the treatment of cerebrovascular disorders. This indication is formulated owing to the affinity of these compounds for alpha and dopaminergic receptors.

The novel therapeuticai use making the object of the present invention is particularly surprising as, contrarily to the other ergot alkaloids, its hydrogenated derivatives have no effect on prolactinaemia in the rat (H. Nasr e O.H. Pearson, Acta Endocrinol. 1975,80,429), while they are endowed only with a weak and short-term effect in the man (Fluckiger E., Del Pozo E., 1980. In: Miller E.E. (Ed.) Neuroactive Drugs in Endocrinology. Elsevier/North Holland Biomedical Press, Amsterdam, pages 169-190).

Dihydroergocristine and dihydroergocryptine resulted to be active in inhibiting, in 100% of the cases, puerperal lactation in the hours subsequent to delivery and for the whole duration of treatment, at doses between 0,5 and 40 mg/die and in a more efficient way than bromocriptine and metergoline.

For example, data regarding milk secretion, mammary congestion and pains in 5 puerperae treated with dihydroergocristine 10 x 2 mg/die versus puerperae treated with bromocriptine 2,5 x 2 mg/die for a week are reported.

The results are reported in the following Table 1 TABLE I MILK SECRETION* Days from delivery DRUG 1st 4th 6th 8th Dihydroergocristine 0,0 0,6 0,33 0,2 Bromocriptine 0,0 0,2 1,86 1,0 MAMMARY CONGESTION AND PAINS* Days from delivery DRUG 1st 4th 6th 8th Dihydroergocristine 0,0 0,8 0,0 0,2 Bromocriptine 0,0 0,2 1,0 0,8 evaluated according to the following scale: 0 = absent; 1 = slight; 2 = moderate; 3 = marked.

While resulting active in inhibiting puerperal lactation, moreover the two compounds have induced none of the peripheral side effects common to other already known ergolinic compounds, due to stimulation of peripheral dopaminergic receptors (for bromocriptine hypotension in 28% and syncope in 0,7% of cases; vomiting in 3% of cases are reported (see Physician's Desk Reference, 36th Edit.: 1684, 1982). Moreover, at least for dihydroergocristine, a dopaminergic antagonist activity was reported (R. Markstein Eur., J.

Pharmacol. 1983).

It is therefore to be considered that the antigalactopoietic activity of hydrogenated alkaloids is not mediated by a stimulation of hypophyseal peripheral dopaminergic receptors, but it is on the contrary directed at the level of the mammary gland.

The validity of the invention is however not tied to the control of the above hypothesized theories and action mechanisms.

The hydrogenated ergot alkaloids can be administered by oral, sublingual or parenteral route, at the dosages of 5-20 mg/die, preferably divided in two administrations.

Adequate pharmaceutical compositions include therefore tablets, capsules, pills, drops, solutions, ampoules, etc. prepared according to pharmaceutical conventional techniques and excipients. For example there can be used excipients like lactose, calcium phosphate, mannitol, starch, kaolin; binding agents like adraquanthin, gelatin, maize starch; lubricating agents like magnesium or calcium stearate, talc; disintegrating agents like alginic acid; edulcorating, colouring, flavouring agents, etc.

The compositions object of the invention can also be of long-term release type, in arder to obtain a retard effect in the absorption of the drug and can also contain other active principles, endowed with known complementary or in any case useful activity. At any rate, the invention covers also those formulations not expressly mentioned but resulting obvious to the relevant experts.

For example, there are reported the following pharmaceutical formulations: 10 mg tablets 1 tablet contains Dihydroergocristine methanesulfonate 10 mg Maize starch 132,6 mg Microgranular cellulose 60,0 mg Lactose 40,0 mg Magnesium stearate 2,4 mg Drops 100 ml contain: Dihydroergocryptine methanesulfonate 200 mg Propylene glycol q.s.

Ampoules Each ampoule contains: Dihydroergocryptine methanesulfonate 0,5 mg Propylene glycol 5,0 mg Methanesulfonic acid q.s. to pH 3 Bidistilled water q.s. to 1,0 ml Capsules One capsule contains: Dihydroergocryptine methanesulfonate 3 mg Starch, lactose, magnesium stearate, microcrystalline cellulose q.s. to 100 mg

Claims (6)

1. The use of an hydrogenated ergot alkaloid, or a pharmaceutically-acceptable salt thereof, in the manufacture of medicaments for use in the treatment of puerperal galactorrhea.

2. A use as claimed in Claim 1, in which the hydrogenated ergot alkaloid is dihydroergocristine or a-dihydroergocryptine.

3. A use as claimed in either of the preceding Claims, in which the hydrogenated ergot alkaloid is employed in the form of the methanesulphonate.

4. A use as claimed in any of the preceding Claims, in which the medicament takes the form of capsules, drops, tablets, or ampoules for intra-muscular or intra-venous administration.

5. A use as claimed in any of the preceding Claims, in which individual doses of the medicament contain from 0.5 to 10 mg of the hydrogenated ergot alkaloid.

6. A use as claimed in any of the preceding Claims and substantially as described hereinbefore.