PHARMACEUTICAL COMPOSITION CONTAINING PYRROLIDONE CARBOXYLIC ACID AND METALLIC SALT FOR USE IN THE TREATMENT OF HEADACHE

BACKGROUND ART

PCA, depicted in Formula 1 below, is a cyclic organic compound, more commonly known as pyrrolidone carboxylic acid or pyroglutamic acid.

Formula 1

In the literature, its action as a vector promoting and improving gastrointestinal absorption of some active ingredients is known.

It is also considered as a natural moisturizing factor (NMF), like urea and lactic acid.

Because of its moisturizing and emollient properties, it is used as an ingredient in various cosmetic compositions, especially as a skin moisturizer and hair conditioner.

When applied on the skin, this compound has no side effects.

Recent publications describe the PCA viral activity against Rhinoviruses following hand application (Journal of Antimicrobial Chemotheraphy 2005, 56, 805-807) as well as antibacterial activity thereof.

Furthermore, in the literature the copper antibacterial activity against bacteria of Staphylococcus aureus e Salmonella thypimurium strains is also known.

In EP2404502B1 the association of PCA with at least one metal salt, preferably a copper, zinc or manganese salt, has been demonstrated to synergistically enhance the PCA antibacterial activity itself and the antiviral activity against influenza viruses, Rhinoviruses and Herpes labialis.

The studies reported in patent application EP2404502B1 and in some publications highlighted that the combination of PCA with metal salt has a synergistic effect on PCA antibacterial and antiviral activity; the synergistic effect occurring when very small amounts of metal salt (2mg/100ml), preferably CuS0 , are added to PCA amounts equal to 4g/100ml.

Headache is a very common and often disabling symptom limiting the performance of normal daily activities.

"Headache" refers to pain experienced in any part of head or neck, which can be a symptom originating from various pathologies.

ICHD-2 classification splits headache into two categories: primary and secondary headaches.

Migraine, tension-type headache, cluster headaches, trigeminal headache, such as the main types of primary headaches, stabbing headaches, coughing headaches, chronic headaches, hypnic headaches and thunderclap headache are defined as primary headaches.

Secondary headaches are classified according to their aetiology and not to their symptoms. According to ICHD-2 classification, the main types of secondary headaches include those resulting from head or neck trauma, such as whiplash injury, an intracranial hematoma, a craniotomy or other head or neck injuries, headache caused by cranial or cervical vascular events, such ischemic attack and transient ischemic attack, non-traumatic intracranial bleed, vascular malformations or arteritis and headaches due to non-vascular intracranial disorders such as low or high cerebrospinal fluid pressure, non-infectious inflammatory disease, intracranial neoplasia, epileptic seizure or other types of intracranial disorders or diseases which are not associated with central nervous system blood vessels. For a complete list of secondary headaches, refer to ICHD-2 classification (International Headache Classification).

Headache in children or cephalea is a more common disorder than you might think; 30% of school-aged children have been estimated to suffer of.

Globally, headache or cephalea prevalence among adults has been estimated to be around 50% (WHO data).

Fortunately, in most cases headache is a temporary and easily treated disorder. However, sometimes it may represent the symptom of even very serious underlying diseases (secondary headache) and it should never be underestimated.

Cephalea is a nonspecific symptom, this means having many possible causes and its treatment depends on etiology, that is, on underlying cause, but commonly involves taking analgesics.

For headache treatment, preferably in children, determining which type of headache the patient is suffering from (primary or secondary) is essential.

For primary headache treatment, the administration of analgesics or non steroidal anti-inflammatory drugs, such as paracetamol (Tachipirina®) or ibuprofen (Brufen, Antalfebal®) is required to relieve pain. In case of secondary headaches, it is very important to identify and therefore treat the underlying cause. For example, in chronic sinusitis headache the treatment involves the intake of antibiotics, in the case of bacterial infections, or antihistaminic, anti-inflammatory drugs and decongestants in the case of viral infections or allergies. However, such drugs do not always have an effect on headache treatment, moreover their prolonged use, especially in children, can have important side effects.

Therefore, there is a need to identify a new drug treatment for headache therapy, in particular for headache therapy in patients with chronic sinusitis, preferably in children.

Definitions

Unless otherwise defined, all the terms of art, notations and other scientific terms used herein are intended to have the meanings commonly understood by those skilled in the art to which this description belongs. In some cases, terms with commonly understood meanings are defined herein for clarity and/or reference; the inclusion of such definitions in this description should not be understood as representing a substantial difference to what is generally understood in art.

The term "simultaneous, separate or sequential use" refers to the simultaneous administration of first and second compounds or in such a way that the two compounds act at the same time in the patient's body or to the administration of one compound after the other compound to provide a therapeutic effect.

The terms "comprising", "having", "including" and "containing" are to be understood as open terms (i.e. the meaning "including, but not limited to") and are to be regarded also as a support for terms such as "to consist essentially of", "consisting essentially of", "to consist of" or "consisting of".

The term "nasal spray" according to the present invention means a solution and/or suspension to be sprayed on nasal mucosa, optionally containing a physiological saline, thermal water or mixtures thereof. Said solution and/or suspension can be isotonic, hypotonic or hypertonic with respect to body fluids. The term "aerosol" according to the present invention refers to a type of colloid wherein a liquid or a solid is dispersed into a gas.

The term "physiologically acceptable excipient refers to a substance without any own pharmacological effects and not producing adverse events when administered to a mammal, preferably a human being. Physiologically acceptable excipients are well known in the art and are described, for example, in Handbook of Pharmaceutical Excipients, current edition, incorporated herein by reference. The term children means a human in "childhood", i.e. that part of the population between 0 (birth) and 18 years.

Description

It has been surprisingly observed that administering, preferably nasally with aerosol, drops or nasal spray, a pharmaceutical composition comprising PCA and metal salts, a complete clearing of headache events in 75% of treated children, a frequency reduction of such headache events in 10% of the cases and a symptom reduction in 90% of the cases is obtained. The therapeutic effect is particularly visible when the pharmaceutical composition of the present invention is administered by aerosol for at least 15 days followed by a subsequent treatment every 15-20 days for at least two months.

An object of the present invention is therefore the use of a pharmaceutical composition comprising PCA, at least one metal salt and at least one physiologically acceptable excipient in the treatment of headache, preferably in patients suffering from sinusitis headache, for example chronic sinusitis, preferably in children.

PCA can be present in the composition for use according to the present invention from 0.0001 to 10% by weight, preferably from 0.001 to 5% by weight, with respect to the total weight of the composition. According to a preferred aspect of the invention, PCA is present in the composition from 0.001 to 4% by weight, with respect to the total weight of the composition, more preferably in an amount equal to about 0.8% by weight.

Preferably, said metal salt is present in the composition for use according to the invention from 0.0001 to 0.05% by weight with respect to the total weight of the composition, more preferably from 0.0004 to 0.001 % by weight with respect to the total weight of the composition, even more preferably in an amount equal to about 0.0004 or 0.002% by weight.

In a further preferred aspect, said metal salt is a copper, zinc or manganese salt, preferably it is a copper salt, more preferably it is copper sulphate, such as for example copper sulphate pentahydrate.

According to a preferred aspect, the pharmaceutical composition to be used in accordance with the present invention is an aqueous solution which may contain, optionally, one or more physiologically acceptable co-solvents, such as for example alcohols, preferably ethanol.

According to a preferred aspect of the invention, said aqueous solution has a pH of 3 and 8, preferably of 4 and 5, even more preferably about 4.5; this pH can be obtained by addition of suitable buffering agents, such as bases, preferably NaOH.

In a preferred aspect the pharmaceutical composition for use according to the present invention may contain a further component.

Said further component is preferably glutaric acid, citric acid, physiological saline, vegetable glycerol, sodium chloride, sodium hydroxide, thermal water, purified water or mixtures thereof. According to a preferred embodiment, the pharmaceutical composition for use according to the present invention contains PCA, copper sulphate pentahydrate, vegetable glycerol, sodium chloride, sodium hydroxide and purified water.

Even more preferably the pharmaceutical composition for use according to the present invention contains the above components in the amounts indicated in Table 1.

Table 1.

^* (about 500 mOsm/kg)

^** (pH= 4-5)

In a further object of the present invention the pharmaceutical composition for use according to the present invention contains the above components in the amounts indicated in Table 2.

Table 2

The composition according to the present invention, preferably the one reported in Table 1 , is administered nasally, preferably in combination with physiological saline in the form of an aerosol, or in the form of a nasal spray.

In a further preferred aspect, the pharmaceutical composition for use according to the present invention is administered nasally in the form of an aerosol in combination with physiological saline, from one to three times a day, preferably twice a day.

Preferably, in the aerosol administration for use according to the present invention, 0.5 ml of said pharmaceutical composition reported in Table 1 in combination with 2 ml of physiological solution are used.

Preferably the pharmaceutical composition for use according to the present invention is administered in the form of an aerosol twice a day, from one to three weeks, preferably twice a day for 15 days.

According to a further preferred aspect, the pharmaceutical composition for use according to the present invention is further administered in the form of an aerosol for 3 or 4 days cycles, 15 or 20 days apart for at least two months.

In a further preferred aspect, after administration in aerosol form of the pharmaceutical composition according to the present invention, said composition is administered in the form of a nasal spray twice a day over a period of at least one month.

Experimental Section

Some formulation examples have been reported in the following tables.

EXAMPLE 1

EXAMPLE 2

EXAMPLE 3

The experimental study was carried out on a sample of 100 children (46 males + 54 females) from 4 to 12 years old; 10 children did not complete the treatment due to non-compliance with therapeutic advice.

The solution used is shown in table 1.

The aerosol was made up as follows: 0.5 ml of single-dose Narlisim (PCA 4% + CuS0 ₄ 2 mg/100ml) with the addition of 2 ml of physiological saline.

All children were suffering from headache following chronic sinusitis.

Aerosol was carried out both in the morning and at night for at least 15 days, continuing with a short cycle (3-4 days) every 15 days for at least two months at the end of which the aerosol was replaced by Narlisim spray with a spray for nostril continuously for 1 month.

The effects of therapy were assessed at the end of the two months therapy.

The results obtained are shown below (the percentages refer to 90 children who completed the treatment):

clearance of headache events: 83.3%;

headache events frequency reduction with symptoms intensity reduction: 1 1 .1 %;

no disease improvement: 5.6%.

EXAMPLE 4.

Performed formulation tests are shown below, the following laboratory available salts were used:

- Manganese(ll) sulphate hydrate

- Zinc Sulphate

- Zinc Chloride

All proposed formulations have pH = 4.5

FORMULATION 1

FORMULATION 2

FORMULATION 3

FORMULATION 4

FORMULATION 5 FORMULATION 6