WO2011067663A1

WO2011067663A1 - Pharmaceutical preparations comprising phloroglucinol and/or derivatives thereof and some non-steroidal anti-inflammatory drugs and their use in the treatment and/or prevention of pain syndromes of the feminine genital system

Info

Publication number: WO2011067663A1
Application number: PCT/IB2010/003109
Authority: WO
Inventors: Cristina CARREÑO SERRAIMA
Original assignee: Diverdrugs Sl
Priority date: 2009-12-04
Filing date: 2010-12-03
Publication date: 2011-06-09
Also published as: ITMI20092151A1; IT1396649B1

Abstract

The invention concerns the use of a pharmaceutical preparation comprising phloroglucinol and/or one of its derivatives and at least one non-steroidal anti-inflammatory compound chosen from meclofenamic acid, nimesulide and etodolic acid, for the treatment and/or prevention of pain syndromes of the female reproductive system.

Description

"PHARMACEUTICAL PREPARATIONS COMPRISING PHLOROGLUCINOL AND/OR DERIVATIVES THEREOF AND SOME NON-STEROIDAL ANTIINFLAMMATORY DRUGS AND THEIR USE IN THE TREATMENT AND/OR PREVENTION OF PAIN SYNDROMES OF THE FEMININE GENITAL SYSTEM"

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SUMMARY OF THE INVENTION

The present invention concerns a combination comprising phloroglucinol and/or its derivatives, and some non-steroidal anti-inflammatory compounds and its use for the treatment and/or prevention of dysmenorrhoea and in general pain syndromes of the female reproductive system, in particular for the treatment of primary dysmenorrhoea.

TECHNICAL FIELD

The term primary dysmenorrhoea identifies the pelvic, abdominal and often also lumbar pain generally associated with the menstrual cycle which is a very widespread phenomenon, since it occurs in almost all women of fertile age.

The symptoms of primary dysmenorrhoea are pain, which in the majority of cases is felt shortly before menstruation and peaks on the first day and possibly the second, tending to diminish from the third day onwards. The pain is often accompanied by nausea, diarrhoea, headache and in some cases even vomiting, dizziness, weakness and lack of appetite.

The exact mechanism of action that generates this pain has not yet been accurately pinpointed. In clinical terms, during dysmenorrhoea an increase in the prostaglandin F2alpha is observed, which leads to a consequent increase in uterine contraction.

One of the main problems associated with the treatment of dysmenorrhoea consists in the fact that the symptomatology, and consequently also the treatment, is repeated chronically every month, throughout a large part of womens' lives. The availability of drugs which are as safe as possible, well tolerated and with a low level of toxicity is therefore obviously important. The current therapies for the symptomatic treatment of dysmenorrhoea comprise the administration of analgesics (opiates), antispasmodics or spasmolytics (antimuscarinics, phosphodiesterase inhibitors, others) or nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs, via different mechanisms of action, lead to improvement of the symptomatology.

In particular, the various NSAIDs block the binding site of the enzymes cyclooxygenase 1 and 2 which regulate the metabolism of the prostaglandins in the tissues.

The aim of the present invention is to provide a pharmaceutical preparation which is particularly effective in preventing and/or treating the pain syndromes of the female reproductive system, dysmenorrhoea and in particular primary dysmenorrhoea.

A further aim of the invention is to provide pharmaceutical preparations comprising different compounds which, operating via different mechanisms of action, lead to a rapid improvement in the symptomatology in patients suffering from dysmenorrhoea.

A further aim of the invention is to provide pharmaceutical preparations for the prevention and/or treatment of dysmenorrhoea which are effective, well tolerated and without toxic effects.

It has now been found that the use of preparations which comprise phloroglucinol, or one of its derivatives, and at least one non-steroidal antiinflammatory drug chosen from meclofenamic acid, nimesulide and etodolic acid, provide an effective and safe treatment of symptomatologies correlated with pain syndromes of the female reproductive system, in particular primary dysmenorrhoea.

DISCLOSURE OF THE INVENTION

Thus according to one of its aspects, the invention concerns a pharmaceutical preparation which comprises

a. at least one compound chosen from phloroglucinol and its derivatives; and

b. at least one non-steroidal anti-inflammatory compound chosen from meclofenamic acid, nimesulide and etodoiic acid

for use in the treatment and/or in the prevention of pain syndromes of the female reproductive system, dysmenorrhoea and in particular primary dysmenorrhoea.

The invention also concerns the preparation, as defined above, for the manufacture of medicaments for the treatment and/or prevention of pain syndromes of the female reproductive system, dysmenorrhoea e in particular primary dysmenorrhoea.

Phloroglucinol is a compound that has been known for some time with a non- anticholinergic aspecific spasmolytic action, widely used in symptomatic treatment of renal, hepatic and biliary colics and in pain syndromes of the female reproductive system, including dysmenorrhoea. Phloroglucinol carries out its spasmolytic action at the level of the vessels, bronchi, intestine, ureters and gall bladder. As a musculotropic spasmolytic, it acts directly on the smooth fibres and behaves as a calcium antagonist at the level of the cell membrane; it causes an increase in the 3'5' AMP by inhibition of the phosphodiesterase.

Phloroglucinol exists in 2 tautomeric forms in equilibrium, the first as 1 ,3,5- trihydroxy-benzene, the second as 1 ,3,5 cyclohexanetrione. Phloroglucinol crystallises as a dihydrate with a melting point of 116-117°C, while the anhydrous form melts at 218-220°C. Phloroglucinol here indicates any one of the two above-mentioned forms.

Derivatives of phloroglucinol here indicate the compounds 1 ,3,5-trimethoxy- benzene and 1 ,3,5-triacetyl-benzene, also known in the art.

Among phloroglucinol and the derivatives of phloroglucinol, phloroglucinol hydrate is particularly preferred.

"Non-steroidal anti-inflammatory compound chosen from meclofenamic acid, nimesulide and etodoiic acid" here also includes their salts, if any, and their isomers or mixtures of isomers, when existing. The salts of the above compounds, when used according to the invention, must be pharmaceutically acceptable. A particularly preferred salt according to the invention is sodium meclofenamate.

The preparation subject of the invention may be in the form of a pharmaceutical composition or a pharmaceutical combination, where:

- "combination" indicates, according to the present invention, that the^ compounds (a) and (b) can be administered separately, provided that administration is practically simultaneous; while

"composition" means, according to the present invention, that the compounds (a) and (b) are included in the same pharmaceutical dosage unit. The preparations of phloroglucinol or its derivatives with the drugs mentioned above, and the specific preparations that follow and those reported in the table and in the examples of the present description, constitute further subject-matter of the invention.

Preferred preparations comprise at least one compound chosen from among phloroglucinol and its derivatives, and at least one compound chosen from meclofenamic acid, nimesulide, etodolic acid and their pharmaceutically acceptable salts.

Meclofenamic acid, in particular in the form of its sodium salt, represents a particularly preferred compound for the combination and composition of the invention.

The preparations of the invention can be administered in the form of dosage units, orally or parenterally, for example intramuscularly, subcutaneously, intravenously, rectally, transmucosally or sublingually.

According to a preferred embodiment, the preparations for the use according to the invention are administered orally or via the buccal route or sublingually, advantageously dosage forms with rapid absorption to obtain immediate relief or controlled release, when a longer period of time has to be covered, for example during the night.

In the case of the combinations according to the invention, the two compounds (a) and (b) can be formulated in different dosage units, according to the different chemical-physical and pharmacodynamic characteristics (absorption, bioavailability, half-life, etc.), according to techniques well known to a person skilled in the art.

Examples of dosage forms suitable for oral administration include, but are not limited to, powders, granules, freeze-dried forms, tablets and capsules. In the preparation of each dosage form, pharmaceutically acceptable excipients can be used, such as excipients, lubricants, binders, disintegrators, emulsifiers, stabilisers, flavour correctors or diluents. Said excipients will be chosen according to the type of pharmaceutical formulation required, as is well known to a person skilled in the art.

Preferred preparations according to the invention are in the form of pharmaceutical compositions.

For the use according to the invention, the preparations in the form of dosage units can comprise from approximately 40 to approximately 160 mg, preferably from 50 to 100 mg, advantageously from 60 to 90 mg, for example around 80 mg of phloroglucinol in hydrated form (corresponding to 62.25 mg in anhydrous form) or one of its derivatives as defined above.

According to a particularly preferred embodiment, the preparations of the invention comprise, in two separate dosage units or, more preferably, in one single dosage unit, as the non-steroidal anti-inflammatory compound, sodium meclofenamate in the amount of 30-80 mg, preferably in the amount of 50- 75 mg (corresponding to 44 and 66 mg of meclofenamic acid).

The preparations of the invention can be administered once or several times a day, according to requirements, the intensity of the pain and the weight of the patient, for example two or three times a day.

The non-steroidal anti-inflammatory compound as defined above can be present in the preparations for use according to the invention according to the posoiogy normally established for said compound, or advantageously also in lower quantities.

In fact a synergic effect has been observed between the phloroglucinol or its derivatives and the non-steroidal anti-inflammatory compounds as defined above, such that it is possible to use lower quantities of the active ingredients than those normally used for the treatment of dysmenorrhoea.

In particular, it has been observed that the phloroglucinol allows a reduction by as much as 50% in the dose of non-steroidal anti-inflammatory compound in the combinations or compositions of the invention, at the same time providing a superior analgesic effect. This fact is particularly important because while the phloroglucinol has a very low toxicity, the non-steroidal anti-inflammatory compounds have, as is known, side effects which can also be serious. Among the undesired effects of the majority of NSAIDs are: inhibition of platelet aggregation with increase in the coagulation time and increase in the menstrual flow.

The same phloroglucinol is used in dosages of approximately 80 mg in the combinations and compositions of the invention, a dose which corresponds to 50% of the dose contained in the drug currently commercially known as SPASMEX ®, which in fact comprises 80 mg of phloroglucinol + 80 mg of a derivative of phloroglucinol, 1 ,3,5 trimethoxy benzene.

By way of example, dosage forms can contain the following combinations:

Phloroglucinol mg NSAIDs mg

80 Sodium meclofenamate 50 - 75

80 Sodium etodolate 200 - 300

80 Nimesulide 50 - 75

Said dosage forms can be administered according to requirements and according to the characteristics of the person to be treated, for example twice or three times a day.

If desired or necessary, it is possible to administer a salt or an isomer or a mixture of isomers of the non-steroidal anti-inflammatory compounds.

Unless indicated otherwise, the quantities given in the present description, in the above table, in the examples and in the claims always refer to the active ingredient in non-salified form.

The preparations according to the invention provide a rapid and effective remedy against dysmenorrhoea, as demonstrated in the experimental section of the invention. The preparations comprising as active ingredients phloroglucinol and meclofenamic acid or its salts are particularly advantageous preparations for use according to the invention. The meclofenamic acid has a high antiinflammatory and analgesic activity, exercised via strong inhibition of cyclooxygenase 1 and 2.

Furthermore, unlike other NSAIDs, it has the singular characteristic of reducing the menstrual flow and at the same time it has little or no effect on platelet aggregation induced by collagen, on the platelet count or on the coagulation time. Furthermore the meclofenamic acid and its salts are quickly absorbed and can thus provide rapid pain relief.

Preparations comprising phloroglucinol and salts of the meclofenamic acid, in dosages lower than those normally present in commercial compositions containing, separately, the same active ingredients, were tested in vivo according to the protocol described in the clinical experimental section of the present invention, and provided excellent results, demonstrating a significant synergy.

In particular a preparation comprising as active ingredients 80 mg of phloroglucinol hydrate and 50 mg of sodium meclofenamate was tested against placebo and against the two drugs commercially available for the treatment of primary dysmenorrhoea: phloroglucinol hydrate 80 mg in orosoluble tablets, and sodium meclofenamate 100 mg in oral capsules. Therapeutic effectiveness and tolerability were verified in a single blind crossover study in volunteer women between the ages of 18 and 45, treated for 4 consecutive menstrual cycles.

The results of the clinical test showed that the preparation according to the invention is more effective in terms of rapidity of action and reduction in the pain symptomatology.

According to another of its embodiments, the invention comprises a method for preventing and/or treating dysmenorrhoea which comprises administering to a person requiring it a preparation as defined in the present description, and in the attached claims, preferably a pharmaceutical composition of the invention.

According to another of its embodiments, the invention concerns a kit which comprises the combination of the invention in which the compounds (a) and (b) are in the form of separate dosage units. Said kit can comprise an instruction leaflet and be appropriately packaged for sale.

The following examples illustrate the invention for non-limiting purposes.

Experimental section

Example 1

Composition in orosoluble tablet form comprising phloroglucinol and sodium meclofenamate.

Phloroglucinol hydrate 80 mg, sodium meclofenamate 50 mg, excipients: mannitol, microcrystalline cellulose, crospovidone, povidone K90, magnesium stearate and aspartame.

Example 2

Composition in oral capsule form comprising phloroglucinol and sodium meclofenamate.

Phloroglucinol hydrate 80 mg, sodium meclofenamate 50 mg, excipients: colloidal silicon dioxide, gelatin, magnesium stearate, microcrystalline cellulose, pregelatinised starch, sodium lauryl sulphate and titanium dioxide. Example 3

Composition in granulate form in sachets comprising phloroglucinol and sodium meclofenamate.

Phloroglucinol hydrate 80 mg, sodium meclofenamate 50 mg, excipients: mannitol, potassium bicarbonate, glycerol, aromas, sodium saccharin.

Example 4

Composition in tablet form comprising phloroglucinol and nimesulide.

Phloroglucinol hydrate 80 mg, nimesulide 50 mg, excipients: lactose, sucrose, magnesium stearate, talc.

Example 5

Composition in tablet form comprising phloroglucinol and etodolac.

Phloroglucinol hydrate 80 mg, etodolac 200 mg, excipients: lactose, sucrose, magnesium stearate, talc.

Example 6

Clinical test for evaluation of effectiveness of a representative composition of the invention:

four formulations were tested comprising, as active ingredient, respectively: Formulation Active ingredient

TEST 80 mg of phloroglucinol hydrate orosoluble tablets + 50 mg

meclofenamic acid sodium salt, capsules;

R1 80 mg phloroglucinol hydrate, orosoluble tablets;

R2 100 mg meclofenamic acid sodium salt, capsules;

P Placebo (orosoluble tablets and capsules, non-medicated).

The 4 treatments were evaluated in 24 women between the ages of 18 and 45 in a single blind crossover 4-way study, for 4 consecutive menstrual cycles. The scheduled treatment dosage was twice a day (bid) with an interval of 12 hours, unless required otherwise by the patient.

To compare the analgesic effect of the TEST treatment compared to the reference treatments R1 and R2 and compared to the placebo (P), in particular their capacity to provide relief from menstrual cramps and pain due to primary dysmenorrhoea. PI was classified according to the following scale: 0= no pain;

1= slight pain;

2= moderate pain;

3= strong pain.

The pain relief (PR) was evaluated as follows:

0= no relief (0% reduction);

1= slight relief (25% reduction);

2= moderate relief (50% reduction);

3= considerable relief (75% reduction);

4= complete relief (100% reduction).

The patients established PI before taking the first dose of composition in each treatment cycle (hour 0) and evaluated PI and PR at regular intervals. The difference in PI and PR at specific time intervals was analysed. The patients also provided an indication of their satisfaction with the treatment, evaluating it on the following scale:

1= poor;

2= average;

3= good;

4= excellent.

Both the pain intensity (PI) and the pain relief (PR) were measured at intervals of 0.5-2 hours in the interval 0-12 hours after the first administration of the first day of treatment, whereas after the administrations of the 2nd and 3rd day of treatment, the measurement was performed at pre-dose, 2, 4, 8 and 12 hours after the morning administrations.

The clinical study results evaluated within the first 12 hours from the first dose in terms of both pain intensity (PI) and pain relief (PR) show the effectiveness of all the treatments in the 24 women evaluated during the 4 successive cycles:

(i) The treatment with placebo reduces the PI from a mean basal score of approximately 2.2 to a value of approximately 1.6-1.7;

(ii) The treatment with phloroglucinol hydrate 80 mg reduces the PI from a mean basal score of approximately 2.2 to a value of approximately 0.9 - 1.1 ;

(iii) The treatment with sodium meclofenamate 100 mg reduces the PI from a mean basal score of approximately 2.2 to a value of approximately 0.8 - 1.0;

(iv) The treatment with phloroglucinol hydrate 80 mg and sodium meclofenamate 50 mg reduces the PI from a mean basal score of approximately 2.2 to a value of approximately 0.5 - 0.7.

Analogously for the PR:

(i) The treatment with placebo shows for the PR, 12 hours after the first dose, a mean score of approximately 1.8-1.9;

(ii) The treatment with phloroglucinol hydrate 80 mg shows for the PR, 12 hours after the first dose, a mean score of approximately 2.5-2.7;

(iii) The treatment with sodium meclofenamate 100 mg shows for the PR, 12 hours after the first dose, a mean score of approximately 2.8-2.9;

(iv) The treatment with phloroglucinol hydrate 80 mg and sodium meclofenamate 50 mg shows for the PR, 12 hours after the first dose, a mean score of approximately 3.4-3.6.

For both the parameters, in relation to the small size of the sample, the differences vs. placebo of the treatments with the single components of the combination were not statistically significant, whereas a significance with p<0.05 was always shown for the combination phloroglucinol 80 mg and sodium meclofenamate 50 mg.

An additive effect of the phloroglucinol on the activity of the sodium meclofenamate administered at a subeffective dose (50 mg instead of the 100 mg scheduled in the current treatment) is therefore evident.

Claims

1. A pharmaceutical preparation comprising:

a. at least one compound chosen from phloroglucinol and its derivatives; and

b. at least one non-steroidal anti-inflammatory compound chosen from meclofenamic acid, nimesulide, etodolic acid, their isomers or mixtures of isomers and their pharmaceutically acceptable salts

for use in the treatment and/or prevention of pain syndromes of the female reproductive system.

2. The preparation as claimed in claim 1 , which is in the form of a pharmaceutical composition.

3. The preparation as claimed in claims 1 or 2, in which said pain syndromes of the female reproductive system are primary dysmenorrhoea.

4. The preparation as claimed in any one of the claims from 1 to 3, characterised in that the at least one compound (a) is phloroglucinol, anhydrous or hydrate.

5. The preparation as claimed in any one of the claims from 1 to 4, characterised in that the at least one compound (b) is meclofenamic acid or its pharmaceutically acceptable salts.

6. The preparation as claimed in any one of the claims from 1 to 6, characterised in that said preparation can be administered orally or by buccal route.

7. The preparation as claimed in any one of the claims from 1 to 7, characterised in that said preparation comprises approximately 40 to approximately 160 mg of phloroglucinol hydrate.

8. The preparation as claimed in claim 8, characterised in that said preparation comprises approximately 80 mg of phloroglucinol hydrate or 62.25 mg of anhydrous phloroglucinol.

9. The preparation as claimed in claim 7 or 8, which comprises between 30 and 80 mg of meclofenamic acid or one of its salts.

10. The preparation as claimed in claim 9, which comprises between 50 mg of meclofenamic acid in the form of sodium salt.

11. A pharmaceutical composition in the form of a single dosage unit, which comprises:

at least one compound chosen from phloroglucinol, anhydrous or hydrate and its derivatives; and

at least one compound chosen from meclofenamic acid, nimesulide, etodolic acid, their isomers or mixtures of isomers and their pharmaceutically acceptable salts.

12. The pharmaceutical composition as claimed in claim 11 , which comprises from 60 to 90 mg of phloroglucinol and from 30 to 80 mg of meclofenamic acid, if necessary in salified form.

13. The pharmaceutical composition as claimed in claim 12, which comprises from 80 mg of phloroglucinol hydrate or 62.26 mg of anhydrous phloroglucinol and 50 mg of sodium salt of meclofenamic acid.

14. The pharmaceutical composition as claimed in claim 12, which comprises from 80 mg of phloroglucinol hydrate or 62.26 mg of anhydrous phloroglucinol and 75 mg of sodium salt of meclofenamic acid.

15. Use of a preparation as defined in any one of the claims from 1 to 9 or a composition as claimed in any one of the claims from 10 to 14, for the manufacture of a medicament for the treatment and/or prevention of pain syndromes of the female reproductive system and dysmenorrhoea.