HK1186671B - Formulations for the treatment of disorders of the upper respiratory tract - Google Patents

Description

Formulations for the treatment of upper respiratory tract disorders

The present invention relates to formulations comprising extracts of Vaccinium myrtillus (Vaccinium myrtillus) or other species rich in anthocyanidins, punica granatum, echinacea and optionally Krameria triandra. The preparation can be used for treating and preventing oral cavity and its adnexa, throat and respiratory tract diseases, and treating influenza.

In particular, the compounds of the invention are particularly useful in bacterial and viral conditions in infants when incorporated in a suitable carrier.

Introduction to

Redness of the throat, inflammation and bacterial and/or fungal infections (plaque formation) are symptoms associated with the common flu, cold and similar conditions. Common cold and influenza, which affect children and adults as many as three times per year on average, are mainly associated with viral infections, 40% of which are caused by rhinoviruses, 10% by coronaviruses, and a small fraction by adenoviruses and parainfluenza viruses.

Prevention and cure of influenza is an important goal, as the disease affects millions of people worldwide each year, with major effects on public health (severe complications that frequently occur can weaken the patient, leading to serious mortality risks) and economics (lost working time).

Influenza is particularly dangerous for elderly people due to complications of influenza or respiratory disorders that elderly patients commonly suffer from. The same problem occurs in infants, wherein a consequence of influenza is a constant cold and recurrence. For many years, prophylactic vaccination has been considered the most effective method of treating viral diseases; however, its efficacy is limited by aberrant antigen mutability, since the emergence of new variants of the virus can outcompete the immunity that can be combated against earlier strains.

While there is no particular treatment for these diseases, antihistamines, decongestants, and anti-inflammatory agents are considered useful because the reduction of edema can relieve pain and shorten the time to the condition causing inflammation. These conditions sometimes involve complications due to the appearance of secondary bacterial infections, since mucosal congestion blocks the sinus exit, allowing pathogenic bacteria to easily multiply therein, causing fever and local pain. In this case, in addition to symptomatic treatment, antibiotic or bacteriostatic treatment is required. However, antibiotics reduce the body's defenses (especially in infants), leading to disease recurrence.

Neuraminidase inhibitors proposed in the last decade also have problems with low efficacy and often toxicity as well as problems causing viral resistance. These substances have different effects on the type a and type b strains, and therefore, when the type of infection cannot be experimentally verified, a substance capable of attacking both strains simultaneously is indispensable.

However, not all commercially available formulations are available for use in children and pregnant women. This means that an antiviral agent which is harmless to both adult patients (including pregnant women) and children and does not cause the appearance of resistant viruses is necessary.

Description of the invention

It has now been found that formulations comprising extracts of vaccinium myrtillus or other species rich in anthocyanidins, pomegranate extract, echinacea extract and optionally peru ratania extract have significant antiviral activity against various strains of influenza a and b, against adenovirus, paramyxovirus, herpes simplex virus, cytomegalovirus and respiratory syncytial virus, and also possess a substantial degree of antibacterial activity and have proven effective for the treatment of conditions of the oral cavity and its appendages, throat and respiratory tract and for the prevention and treatment of influenza.

Accordingly, the present invention relates to a novel formulation comprising:

a) extracts of vaccinium myrtillus or other species rich in anthocyanidins;

b) an extract of pomegranate;

c) echinacea purpurea extract;

and optionally

d) Krameria triandra extract.

According to the invention, the term "vaccinium myrtillus or other species" includes plants containing anthocyanosides. The anthocyanidins present in these plants are mainly anthocyanidins and delphinidin glucosides, which have been described for their activity in capillary protection, inflammation, angiogenesis and immunomodulation.

The anti-inflammatory effects produced by anthocyanidins are linked to NFkB inhibition and their anti-angiogenic capacity, these parameters were evaluated and activity was found at nanomolar level, since the angiogenic process is essential for inflammation and angiogenesis is dependent on VEGF (vascular endothelial growth factor). The molecules also inhibit 5-and 12-lipoxygenase at nanomolar concentrations. Anthocyanins and tannins and their metabolites can significantly inhibit the nuclear factor NF-kB, which is involved in both inflammation and immune responses to infection, and also inhibit this factor at nanomolar concentrations.

According to the invention, the pomegranate extract is an extract obtained from the fruit having a polyphenol content of 90%. The extract has proven antiviral and moderately antibacterial properties and can enhance the body's defenses by increasing interferon gamma synthesis.

The extract is prepared by extracting the fruits and/or aerial parts of the plant with various dilutions of a C1-C3 aqueous alcoholic dilution, preferably a 50% v/v ethanol/water mixture, subsequently concentrating the aqueous/ethanol extract until the organic solvent is completely removed, treating the turbid suspension with 0.2% by weight of the plant material of polyvinylpyrrolidone, filtering to remove unwanted polymeric tannins, adsorbing the clear solution onto a polystyrene resin and washing the resin until the soluble material is completely removed. The active ingredients constituting the extract used in the present invention were recovered by washing the resin with 90% ethanol. Concentrating the ethanol eluate to a small volume and vacuum drying the residue at a temperature not exceeding 50 ℃ to obtain a polyphenol-rich extract.

According to the invention, the Echinacea extracts are preferably alcoholic extracts of the roots and aerial parts of Echinacea angustifolia (Echinacea angustifolia) and/or Echinacea angustifolia (Echinacea purpurea).

The antibacterial and antiviral activity of Echinacea extracts has been documented, in particular against Streptococcus pyogenes, Staphylococcus aureus (penicillin resistant), Haemophilus influenzae and Legionella pneumophila. These activities are associated with the polyphenol fraction and the lipophilic fraction of the isobutylamides rich in polyunsaturated acids (phytomedine, 17,563,2010). Isobutylamides are potent ligands for the cannabinoid and capsaicin TRPV1 receptors and thus may have effects on pain, inflammation, and immune responses. Recently, it has been demonstrated with cannabis derivatives that cannabinoid agonist compounds have also been associated with the potentiation of immune responses.

According to the invention, the Krameria triandra extract is an aqueous/alcoholic extract obtained from the roots and aerial parts of the plant, purified according to the method described previously for the preparation of pomegranate extract. The obtained Krameria triandra extract has a benzofuran content of 14% and ellagitannins and protocatechuin content of 70%. Krameria extract is known to have antibacterial and antifungal activity at concentrations of mg/mL.

It has now been found, surprisingly, that the formulations of the invention have antibacterial and antiviral activity which significantly exceeds that of the extracts when administered separately, suggesting that there is an empirically unpredictable in vivo synergistic mechanism in terms of therapeutic and prophylactic effect, which enhances the antibacterial and antiviral activity of the substance in particular.

The formulations of the invention have been shown to be highly active against the most common viral strains, in particular influenza viruses, and to prevent the formation of bacterial plaques and fever common to cold and influenza. These preparations are also effective against suppurative otitis and general oral infections.

According to a preferred aspect, the formulation of the invention contains, per unit dose, the active ingredients within the following weight intervals:

a) 20 to 80mg of an extract of vaccinium myrtillus or other species rich in anthocyanidins;

b) 20-40 mg of pomegranate extract;

c) 20 to 100mg of echinacea extract;

and optionally

d) 10-30 mg of Krameria triandra extract.

According to a particularly preferred aspect, the compositions of the invention contain, per unit dose, the following active ingredients in the following weight ranges:

a) 40 to 60mg of extract of vaccinium myrtillus or other species rich in anthocyanidins;

b) 25 to 35mg of pomegranate extract;

c) 40-60 mg of echinacea extract;

and optionally

d) 15 to 20mg of Krameria triandra extract.

The pharmaceutical preparations to be used are mainly formulated as tablets which dissolve slowly in the oral cavity or as chewing gums which release the active ingredient slowly. These formulations are primarily intended for prophylactic treatment, but can also be used for curative treatment, and can be used for oral hygiene.

Thus, the formulations are prepared according to well-known conventional methods, for example, as described in "Remington's pharmaceutical handbook", Mack Publishing co., n.y., USA, together with suitable excipients.

The following examples illustrate the invention in detail.

Example I-A1000 mg chewable tablet comprising the following ingredients

Example II-A1000 mg chewable tablet comprising the following ingredients

Example III-particles for the in situ preparation of a suspension comprising the following ingredients:

example IV-particles for the in situ preparation of a suspension comprising the following ingredients

Example V biological Activity

The compositions of the invention were tested in 6 groups of 10 patients with oral bacterial infections, each group being of both sexes.

Patients were treated with tablets containing the combination (example II) or tablets containing the single ingredients 3 times daily for 3 days. Pharyngeal and tonsillar congestion was assessed on a 4 point scale (no =0, mild =1, moderate =2, severe =3) 1 hour prior to the first treatment and 1 hour after the last treatment.

The results are shown in Table 1.

TABLE 1

Meanwhile, the patient gargles with 10mL of sterile distilled water for 20 seconds, and the sample was collected.

The sample was suitably diluted in ringer's solution containing 0.2% dithiothreitol, and 0.5ml was dilutedPlacing the solution in 4 agar plates (Columbia) added with 5% sheep blood; placing the plate on CO₂The anaerobic culture was carried out by keeping the temperature for 72 hours in the atmosphere. After incubation, the number of colonies was counted.

The results are shown in Table 2.

TABLE 2

Claims (3)

1. Formulations for the treatment and prevention of disorders of the oral cavity and its appendages, the throat and the respiratory system and influenza, comprising as the only active ingredients the following ingredients in the following weight ranges per unit dose:

a) 20 to 80mg of vaccinium myrtillus extract;

b) 20-40 mg of pomegranate extract;

c) 20 to 100mg of echinacea extract;

and optionally

d) 10 to 30mg of Krameria triandra extract,

wherein the extract of Vaccinium myrtillus comprises anthocyanins and delphinidin glucoside,

wherein the pomegranate extract is an extract obtained from fruit having a polyphenol content of 90%,

wherein the Echinacea extract is an alcoholic extract of the roots and aerial parts of Echinacea angustifolia and/or Echinacea purpurea, and

wherein the Krameria triandra extract is an aqueous/alcoholic extract obtained from roots and aerial parts of plants, and has a benzofuran content of 14% and ellagitannins and protocatechuins content of 70%.

2. The formulation of claim 1, comprising active ingredients in the following weight ranges per unit dose:

a) 40-60 mg of vaccinium myrtillus extract;

b) 25 to 35mg of pomegranate extract;

c) 40-60 mg of echinacea extract;

and optionally

d) 15 to 20mg of Krameria triandra extract.

3. Use of a formulation according to claim 1 or 2 for the manufacture of a medicament for the treatment and prevention of disorders of the oral cavity and its appendages, throat and respiratory system and influenza.