EP0805679A1

EP0805679A1 - Therapeutical use of beta-mimetic agents for the transmucosal treatment of dysmenorrhoea

Info

Publication number: EP0805679A1
Application number: EP95941150A
Authority: EP
Inventors: Christophe Boyer; Bertrand Galichon
Original assignee: Individual
Current assignee: Individual
Priority date: 1995-11-28
Filing date: 1995-11-28
Publication date: 1997-11-12
Also published as: WO1997019680A1

Abstract

A novel therapeutical use of β-mimetic agents for preparing a drug suitable for treating or alleviating dysmenorrhoea is disclosed. The pharmaceutical forms used contain 0.1-10 mg of a β-mimetic agent combined with one or more non-toxic inert excipients or carriers suitable for transmucosal delivery. The β-mimetic agent may be combined with an antiarrhythmic agent, a bradycardiac agent or an anti-inflammatory agent.

Description

Therapeutic use of betamimetric agents to treat menstrual pain by pus

The present invention relates to the field of therapy and more particularly to the field of gynecological therapy

More specifically, it relates to a new use of a betamimetic medicament intended for the treatment or the relief of gynecological disorders by administration by the mucosal route.

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The invention relates in particular to the use of betamimetics agents for the production of a medicament intended for the treatment or relief of dysmenorrhea or algomenorrhea, characterized in that said β-mimetic agent is administered in one of the forms which are suitable for one of the n mucous membranes and, in particular, for the pernasal

The new route of administration of β-mimetic agents makes it possible to produce a drug intended to suppress or reduce menstrual pain without any troublesome or undesirable cardiac or pulmonary effect.

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The mucous membrane includes the application of the drug to one of the accessible mucous membranes for therapeutic treatment and in particular the nasal mucosa and the sublingual mucosa.

2 * We have known for a very long time that the onset of menstruation is accompanied beforehand by a period of tension, nervousness or more or less painful congestion which is. usually, treated with anti-inflammatory agents, because linked to the rise in the level of prostaglandiπes is mainly pain more or less acute at the time of menstruation, and which are linked to a

M ⁾ hypercontractibility of the uterine lining In an older era, many women, during menstruation, were forced to lie down or had to take painkillers whose effectiveness could not be proven

The use of peripheral analgesics such as pyramidoπ glafenine and above all noramidopyπne as well as non-steroidal anti-inflammatory drugs, inhibitors of prostaglandin synthesis and usual mode of treatment of dysmenorrhea, is not without disadvantage, nor without risk for health Similarly, the use of plant or synthetic spasmolytics has a transient and rapid action ineffective. We also recommended the use of myo-relaxants such as racefemme, which can sometimes lead to insomnia and psychotonic actions.

But above all, an article by M. DELECOUR (Sem. Hôpital. Paris 1984 - 60) highlights the fact that β-mimetics (Ritodrine or salbutamol) bring on bothersome side effects, such as palpitations and tremors and above all are not suitable. for subjects with the usual contraindication of β-mimetics (heart disease, asthma, diabetes).

All these symptomatic therapies have been found to act on pain when they occur, but the effect is transient and after success, the algomenorrhea can recur, much more intense.

Similarly, the hormonal treatment of these syndromes involves a number of vascular and metabolic risks. It is often the cause of intolerance or skin problems.

In the absence of an effective and lasting drug, it was preferable, for dysmenorrheic subjects, that this period be spent at rest and even in the lying position.

The active life that many women lead today and the imperatives of work are incompatible with this type of constraint. It was therefore necessary, for a certain number of women, who every month, at the time of the menstrual period, experiencing particularly painful periods, to accept to know three or four days when they will have to endure pronounced uterine pain, either d '' use an effective drug without side effects, which allows them to overcome this painful period, or better yet, to see this period disappear.

It is known that β-mimetic agents are conventionally divided into β-1 mimetic agents and into β-2 mimetic agents according to whether they stimulate the cardiac adrenergic receptors (β-1 agents) or the pulmonary adrenergic receptors (β-2 agents mimetics). Not all β-mimetic agents are necessarily selective and may act preferentially either on the β-1 receptors. either on the β-2 receptors. without being inactive on receptors of the other type. They can also be partial agonists of the β- 1 and β-2 receptors This is why, it is possible to add to the β-mimetic agents, compounds of the β-blocker type which have, in addition, an intrinsic action, activating more or less pronounced on the β receptors. An example of these mixed type agonists is in particular a blocking β-2 such as Labetalol or INPEA These compounds therefore have a stimulating β-2 action in addition to their blocking β-2 action, causing a certain slowing of the rhythm cardiac, specific to β-2 blockers. However, it is found that they cause the effects specific to β-mimetic agents while being more limited.

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There is, therefore, a wide variety of β-mimetic agents, some are specific for β-2 receptors, others have a more general action on β receptors. Thus we can cite terbutaline which is a selective β-2 mimetic agent and which acts essentially on bronchial receptors,

15 albuterol (salbutamol), which is as selective as terbutaline and whose pharmacological properties and known therapeutic indications, are similar to those of terbutaline, the isoethane whose degree of selectivity is slightly lower, penbuterol whose β-2 agonist activity is relatively selective, bitolterol and its sets, which constitutes a pro-drug of another β-mimetic agent colterol, 0 bambuterol which is a chemical derivative of salbutamol of which it has substantially the pharmacological properties , fenoterol, ritodrine, salmeterol, tulobuterol, mabuterol and GR-6341 1.

The object of the present invention is therefore a medicament which suppresses the painful phenomena of the menstrual period without causing neither hormonal phenomena nor effects on the central nervous system and whose effectiveness is rapid and constant. This could be achieved by using for this therapeutic purpose, a β-mimetic agent and mainly one of those mentioned above, administered by the mucosa and especially by the pernasal route. 0

As a result, anti-dysmenorrhea drugs have no central effects like conventional analgesics and have no influence on the course of the menstrual period.

Î> According to the invention, the pharmaceutical forms contain from 0.1 to 10 mg of a β-mimetic agent administered from one to three times a day during the menstrual period. The preference will go to active principles of longer duration of action. long like bambuterol or bitolterol and so it will be possible to reduce the number of doses However, salbutamol, although its action is shorter, has the advantage of greater speed of action and thus results in faster relief.

Tests carried out using a β-mimetic agent and in particular salbutamol, have moreover shown the speed and effectiveness of the action of these drugs Tested on patients who felt the acute pain typical of algomenorrhea, the administration permuqueuse (or sub-lmguale) of 200 pg of drug led to the following results.

• in the case of patients who had not taken any prior treatment, the reduction in pain amounted on average to 42%, 10 minutes after administration and to 57%, 20 minutes after this same intake for almost all of the patients.

Note: it would perhaps be interesting to obtain the results generated by a conventional treatment alone (anti-inflammatory, analgesic and / or anti-spasmodic non-b-mimetic) in order to be able to compare the results with those of the only administration of salbutamol .

• with regard to tests carried out on patients who had used, before the administration of salbutamol, another treatment (analgesic, anti-inflammatory and / or anti-spasmodic, other than a β-mimetic agent) , but that they considered insufficiently effective, the improvement felt is on average around 56% from the 10 minutes after taking it, and 79%, 20 minutes after this same taking. In the latter case, the performance obtained both in terms of the speed and effectiveness of pain relief, most likely suggests synergy.

The medicaments according to the invention are administered in one of the forms suitable for mucosal administration. In this regard, mention may be made of solutions or suspensions propelled by an inert propellant gas and gels to be applied to the nasal mucosa. Preferably, a solution or suspension intended for the pernasal route is used, administered under propellant gas pressure or under ambient air pressure.

In a preferred manner, the content of active principle will range from 0.2 to 5 mg per unit intake. The dosage depends on the intensity of the pain, the speed of action of the active ingredient, the duration of its action and the route of administration

The medicaments according to the invention contain, in addition, one or more inert excipients or vehicles, non-toxic, suitable for the abovementioned route of administration. In this regard, adhesion agents such as modified or unmodified celluloses may be mentioned. , lactose, sorbitol, palatinite, carbonates or phosphates of alkaline earth metals or magnesium, fatty substances, polar solvents which allow or facilitate the passage of mucous membranes such as cyclic ketones, cyclic lactams, bile acids and their hydrogenated derivatives.

The medicament according to the invention finds a therapeutic use for the attenuation of primary dysmenorrhea, secondary dysmenorrhea consecutive to a trauma, an inflammation or an infection of the appendages 15 and also in the case of endometπosis at least as an adjuvant of the usual treatment, especially hormonal.

The β-mimetic agent can be added with an anti-arrhythmic or bradicardizing agent such as quinidine or an anti-inflammatory agent such as Mefenamic acid or Flufenamic acid.

The solute is supplemented with isotonic substances such as mineral salts, anti-bacterial substances which guarantee microbial cleanliness, complexing agents, buffering substances or even reducing substances.

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The nasal gel is preferably formed from a very viscous aqueous solution or dispersion of Carbomer and in particular of acrylic polymer sold under the brand Carbopol.

M ⁾ The medicament according to the invention can also be in the form of tablets intended to be placed under the tongue and to dissolve on contact with saliva.

CLINICAL OBSERVATIONS ι> Summary and Presentation

Effect of salbutamol in sublingual administration in the treatment of dysmenorrhea This observation is the result of a collection of "emergency" visits. There was no draw and it is not a randomized study.

The efficacy of salbutamol spray (two puffs, i.e. 200 micrograms of salbutamol) is only considered in relation to the treatment preceding the visit or, failing this, in relation to itself The patient coast on a segment of the right subjective improvement she feels. No visual scale was used.

The sample size is 15.

Were included, all patients who experienced pain typical of uterine colic, either by the academic description they made of it, or by the obvious resemblance to their usual pre-menstrual pain.

9 out of 15 patients were dramatically improved at 20 minutes compared to their usual treatment taken before.

4 patients who had taken nothing before the administration of ventoline experienced a significant improvement.

• 2 failures are also refractory to any conventional treatment. Failure is due to an anxiety attack.

When the patient did not take any treatment before the arrival of the doctor, the results remain honorable (effect at 20 min greater than 50% on average), while being less. One can imagine that the classic treatment is synergistic to that which was carried out.

Results

9 out of 15 patients are dramatically improved by a standard intake of two puffs of salbutamol sublingual, whereas they had already used another treatment before the doctor came

One of the patients improved little after 10 min and then returned almost to its initial state (only 10% improvement). She was, in fact, showing signs of an acute anxiety attack which probably distorted the appreciation of the pain

The worst score is obtained in a patient who will remain refractory to any treatment (see below)

The other 2 patients are nevertheless relieved by 40% of their pain after 20 minutes

One case is interesting in that the administration of salbutamol like the IV injection of Avafortan ^R remained ineffective (0%) and that only the IV injection of Valιum ^R was found to be beneficial Another case shows that if the treatment tested proved ineffective (30% and 10% at 20 min), conventional treatment could not do better

CONCLUSIONS

On the small number of cases of observation, treatment failures are strongly correlated with the presence of symptoms of acute physical anxiety.

In 9 out of 15 cases, there is an obvious improvement in pain compared to the usual treatment taken before the doctor's visit and the administration of sublingual salbutamol.

These results strongly suggest that Salbutamol in a low dose administration of mucosal agents is effective in treating dysmenorrhea validly, and this in the absence of undesirable effects in this study.

Claims

1. New use of a β-mimetic agent for the production of a medicament reducing or eliminating menstrual pain, characterized in that it comprises said β-mimetic agent, in combination or in mixture, with a vehicle or an inert excipient suitable for the route of administration of the mucosa.

2. New use of a β-mimetic agent for the production of a drug reducing or eliminating menstrual pain, based on a β-mimetic agent according to claim 1, characterized in that the active principle is associated or mixed with an inert vehicle or excipient suitable for the pernasal route of administration.

3. New use according to claim 1 in which the medicament contains an effective amount of a β-mimetic agent to bring about sedation or the disappearance of menstrual pain.

4. New use according to claim 1 or claim 2 in which the effective amount of a β-mimetic agent ranges from 0.1 to 10 mg per unit dose.

5. New use according to one of claims 1 to 3 ° in which the content of active principle preferably ranges from 0.2 to 5 mg per unit intake.

6. New use according to one of claims 1 to 4 ^ύ in which the β-mimetic agent is chosen from the group consisting of salbutamol and its esters, pirbutol, bitolterol, colterol, ritodπne, terbutaline, fenoterol, salmeterol, tulobuterol, mabuterol and GR 6341 1

7. New use according to one of claims 1 to 5 ° in which the β-mimetic agent is a β-blocking agent having an intrinsic β-mimetic activity

8. New use according to one of claims 1 to 6 ° in which the β-mimetic agent is added with another active principle chosen from the group formed by an anti-arrhythmic agent, a bradycardia agent and d 'an anti-inflammatory agent.

9. New use according to one of claims 1 to 7 ° in which the medicament which reduces or eliminates menstrual pain is formed of a β-mimetic agent in solution or in suspension in an inert non-toxic vehicle, suitable for the route of administration, either in the form of a mucous membrane or in solid form.

10. New use according to claim 8 in which the solution or the suspension is added with an isotonizing agent and / or a buffering agent and / or a preservative and / or a complexing agent.

11. New use according to claim 8 or claim 9 in which the solution or the suspension is introduced into an airtight bottle whose internal pressure is greater than atmospheric pressure.