FR3115683A1 - Antiseptic composition for nasal administration - Google Patents

Abstract

The invention relates to a composition for use as a medicine comprising at least silver in colloidal form, an extract of Sambucus Nigra, an extract of Primulae flos cum calycibus, an extract of pelargonium sidoides. Preferably, said composition is used in prophylaxis and/or antiviral, antibacterial and antifungal treatment.

Description

Antiseptic composition for nasal administration

The invention relates to a composition for use as a drug comprising at least silver in colloidal form, an extract of Sambucus Nigra, an extract of Primulae flos cum calycibus, an extract of pelargonium sidoides. Preferably, said composition is used in antiviral, antibacterial and antifungal prophylaxis and/or treatment.

The invention relates to the field of antifungal, antiviral and antibacterial treatments.

PRIOR ART

The therapeutic properties of silver were already known at the time of ancient Greece: it was known that in families where silver cutlery was used to eat, infections were less frequent. Silver has significant antimicrobial properties since the presence of one part in 100 million of elemental silver in solution is sufficient to obtain an effective antimicrobial action. It is also well known that silver ions or free radicals are an active antimicrobial agent.

To make silver soluble in water, it is necessary to use a colloidal ionic form (a suspension in water of extremely fine silver particles), which was first obtained in 1920 thanks to a hydrolysis process in which two pure silver electrodes are used, immersed in demineralised or distilled water, to which a potential difference is applied.

Before the appearance of antibiotics in 1938, the colloidal silver thus obtained was prescribed for a wide variety of diseases and infections: indeed, it had been proven to be effective against more than 650 different pathogens.

Colloidal silver makes it possible to improve the functioning of the immune system, because it acts as a catalyst, by deactivating the specific enzymes necessary for the metabolism of many bacterial, fungal and viral species.

This success is due to the fact that it is a safe antiseptic; in fact, when used in colloidal form, silver is absorbed very slowly by the tissues so as not to cause toxic effects. It can therefore be taken orally and be part of the preparations which can be taken daily by adults and children without the risk of the appearance of any intolerance, even if the use is prolonged over time.

Colloidal silver is mainly used as an antiseptic in dermatology for the treatment of certain types of lesions. It is also known for its application as a potabilizing agent for water and as a preservative in the cosmetics industry.

However, colloidal silver is not effective against all fungi, viruses and bacteria.

Today, and even more so since the global epidemic linked to the SARS‐CoV‐2 virus, there remains the need for an alternative to existing compositions, which is effective against all existing and future pathogenic viruses, fungi and bacteria. .

Unexpectedly, the applicant discovered that the combination of colloidal silver with several plant extracts resulted in an effective composition in antiviral, antibacterial and antifungal prophylaxis and treatment.

DETAILED DESCRIPTION OF THE INVENTION

• De l’argent sous forme colloïdale ;
• Un extrait de Sambucus Nigra ;
• Un extrait de Primulae flos cum calycibus ;
• Un extrait de pélargonium sidoides.

Thus, according to a first aspect, the invention relates to a composition for use as a medicament comprising:

• Silver in colloidal form;
• An extract of Sambucus Nigra;
• An extract of Primulae flos cum calycibus;
• An extract of pelargonium sidoides.

By colloidal ionic silver is understood according to the invention a suspension in water of extremely fine silver particles.

Preferably, said silver in colloidal form has a particle size of between 0.1 and 30 nanometers.

• Entre 20 mg et 250 mg d’argent sous forme colloïdale par litre de composition.

Preferably, said composition for use according to the invention comprises:

• Between 20 mg and 250 mg of silver in colloidal form per liter of composition.

By convention, it is generally considered that 1mg of silver is equivalent to 1ppm in a 1 Liter solution, i.e. 20mg to 250mg per liter of solution.

Sambucus Nigra, or Black Elder, is a shrub-like plant from the Caprifoliaceae family. The extracts from this plant can come from its flowers or its fruits, and be dry, aqueous and/or alcoholic extracts.

• Entre 0,3 et 5% en poids de la composition d’Extrait de Sambucus Nigra.

Preferably, said composition for use according to the invention comprises:

• Between 0.3 and 5% by weight of the Sambucus Nigra Extract composition.

Primulae flos cum calycibus, or Primrose officinale is a perennial herbaceous plant of the Primulaceae family. Said extracts come from grinding the flowers and/or calyx of this plant, optionally in water and/or alcohol. These extracts can also be dry extracts.

• Entre 1 et 9% en poids de la composition d’Extrait de Primulae flos cum calycibus.

Preferably, said composition for use according to the invention comprises:

• Between 1 and 9% by weight of the composition of Primulae flos cum calycibus extract.

Pelargonium sidoides, or Umckaloabo, is a plant native to South Africa. Extracts from this plant can take the form of dry, aqueous and/or alcoholic extracts of the roots or other parts of the plant.

• Entre 1 et 6% en poids de la composition d’Extrait de pélargonium sidoides.

Preferably, said composition for use according to the invention comprises:

• Between 1 and 6% by weight of the composition of Pelargonium sidoides extract.

• Entre 20 mg et 250 mg d’argent sous forme colloïdale par litre de composition.;
• Entre 0,3 et 5% en poids de la composition d’Extrait de Sambucus Nigra ;
• Entre 1 et 9% en poids de la composition d’Extrait de Primulae flos cum calycibus ;
• Entre 1 et 6% en poids de la composition d’Extrait de pélargonium sidoides.

According to one embodiment, said composition for use according to the invention comprises:

• Between 20 mg and 250 mg of silver in colloidal form per liter of composition;
• Between 0.3 and 5% by weight of the Sambucus Nigra Extract composition;
• Between 1 and 9% by weight of the composition of Primulae flos cum calycibus extract;
• Between 1 and 6% by weight of the composition of Pelargonium sidoides extract.

• De l’argent sous forme ionique ;

According to one embodiment, said composition for use according to the invention further comprises:

• Silver in ionic form;

By ionic silver is understood according to the invention silver whose particles have been dissolved in water, on the contrary colloidal silver where said particles are in suspension in water.

• Entre 20 mg et 250 mg d’argent total par litre de composition, réparti en
  1. Entre 70 et 99,99% en poids total d’argent, d’argent sous forme colloïdale ;
  2. Entre 0,01 et 30% en poids total d’argent, d’argent sous forme ionique.

According to one embodiment, said composition for use according to this latter embodiment comprises:

• Between 20 mg and 250 mg of total silver per liter of composition, divided into
  1. Between 70 and 99.99% by total weight of silver, silver in colloidal form;
  2. Between 0.01 and 30% by total weight of silver, silver in ionic form.

By total silver is understood according to the invention all of the silver included in the composition according to the invention, whatever its form.

• Entre 20 mg et 250 mg d’argent total par litre de composition, réparti en
  1. Entre 70 et 99,99% en poids total d’argent, d’argent sous forme colloïdale ;
  2. Entre 0,01 et 30% en poids total d’argent, d’argent sous forme ionique ;
• Entre 0,3 et 5% en poids de la composition d’Extrait de Sambucus Nigra ;
• Entre 1 et 9% en poids de la composition d’Extrait de Primulae flos cum calycibus ;
• Entre 1 et 6% en poids de la composition d’Extrait de pélargonium sidoides.

According to one embodiment, said composition for use comprises:

• Between 20 mg and 250 mg of total silver per liter of composition, divided into
  1. Between 70 and 99.99% by total weight of silver, silver in colloidal form;
  2. Between 0.01 and 30% by total weight of silver, of silver in ionic form;
• Between 0.3 and 5% by weight of the Sambucus Nigra Extract composition;
• Between 1 and 9% by weight of the composition of Primulae flos cum calycibus extract;
• Between 1 and 6% by weight of the composition of Pelargonium sidoides extract.

• Un extrait d’Echinacea, et/ou
• De la Propolis et/ou
• Un extrait d’Artemisia et/ou
• Un extrait d’Allium sativum.

According to one embodiment, said composition for use according to the invention further comprises:

• An extract of Echinacea, and/or
• Propolis and/or
• An extract of Artemisia and/or
• An extract of Allium sativum.

Echinacea, or Echinacea, refers to a genus of plants from the Asteraceae family. Said extracts take the form of dry, aqueous and/or alcoholic extracts, produced from the root, the whole plant or the aerial parts.

• Entre 0,01 et 8% en poids de la composition d’extrait d’Echinacea.

Preferably, said composition for use according to the invention comprises:

• Between 0.01 and 8% by weight of the Echinacea extract composition.

Allium sativum, a plant more commonly known as "garlic", is a perennial plant species. Extracts can take the form of a dry, aqueous and/or alcoholic extract, or an aged garlic extract.

• Entre 0,01 et 10% en poids de la composition d’extrait d’Allium sativum.

Preferably, said composition for use according to the invention comprises:

• Between 0.01 and 10% by weight of the Allium sativum extract composition.

“Propolis” is a product derived from plant resins and exudates, which can be secreted by plants or made by bees from plant resin and wax. As propolis depends on the species of plants from which it is produced, standardized propolis is produced, often defined by their color. Preferably, yellow, green or red propolis will be used here. Said propolis can be presented in the form of a dry, purified, aqueous and/or alcoholic extract.

• Entre 0,01 et 7% en poids de la composition de propolis.

Preferably, said composition for use according to the invention comprises:

• Between 0.01 and 7% by weight of the propolis composition.

Artemisia or Mugwort is a genus of plant species comprising herbaceous plants, shrubs and shrubs, with pinnate leaves. Preferably, the species used according to the invention is Artemisia annua. The latter is an aromatic branched herbaceous plant. Extracts from this plant can come from the whole plant or from the aerial parts, and be dry, aqueous and/or alcoholic extracts.

• Entre 0,5 et 3% en poids de la composition d’extrait d’Artemisia.

Preferably, said composition for use according to the invention comprises:

• Between 0.5 and 3% by weight of the Artemisia extract composition.

• Entre 0,01 et 8% en poids de la composition d’extrait d’Echinacea, et/ou
• Entre 0,01 et 7% en poids de la composition de Propolis, et/ou
• Entre 0,5 et 3% en poids de la composition d’extrait d’Artemisia, et/ou
• Entre 0,01 et 10% en poids de la composition d’extrait d’Allium sativum.

Preferably, said composition for use according to the invention comprises:

• Between 0.01 and 8% by weight of the Echinacea extract composition, and/or
• Between 0.01 and 7% by weight of the Propolis composition, and/or
• Between 0.5 and 3% by weight of the Artemisia extract composition, and/or
• Between 0.01 and 10% by weight of the Allium sativum extract composition.

Preferably according to the invention, said composition for use according to the invention comprises at least one other dermatologically and/or pharmaceutically acceptable agent.

According to one embodiment, said composition for use according to the invention is intended to be used in prophylaxis and/or antiviral, antibacterial and antifungal treatment.

Preferably, said composition for use according to the invention can be administered orally, intravenously, subcutaneously, nasally, ophthalmically, auricularly, rectally, vaginally, by respiratory , or by application to the skin.

Even more preferably, the oral route can take the form of a tablet, a syrup, a drinkable solution or suspension, a capsule,

Even more preferably, the intravenous route can take the form of a solution.

Even more preferably, the subcutaneous route can take the form of a solution.

Even more preferably, the route of application to the skin can take the form of an ointment, a cream, a patch or a gel.

Preferably, the administration is carried out by the respiratory or nasal route.

Preferably, said composition for use according to the invention is administered by the respiratory or nasal route, in the form of nasal drops, nasal spray, nasal powder, aerosol, for example compressed gas aerosols and/or nasal spray , or a nebulizer.

Advantageously, when the pharmaceutical composition is suitable for nasal or respiratory administration, it can advantageously be for broncho-pulmonary or sinus purposes.

Preferably, said composition for use according to the invention is administered by aerosol in the nasal passages.

The composition according to the present invention can be administered to a patient daily, once a day, twice a day, three times a day or even more times a day. Preferably, the composition of the present invention is administered to a patient twice a day and every 12 hours.

• Eau Purifiée de grade pharmaceutique : qsp
• 20 mg d’Argent au total à hauteur de 20% d’argent sous forme ionique et 80% d’argent sous forme colloïde, de taille de particule moyenne 0,8nm ;
• 0,9% d’extrait de Sambucus Nigra ;
• 5% d’extrait sec Primulae flos cum calycibus ;
• 1,5% d’extrait sec Pélargonium sidoides ;
• 3% extrait sec Echinacea ;
• 4% extrait purifié Propolis.

According to one embodiment of the invention, said composition comprises, by weight of the composition:

• Pharmaceutical grade Purified Water: qsp
• 20 mg of silver in total up to 20% silver in ionic form and 80% silver in colloid form, with an average particle size of 0.8 nm;
• 0.9% Sambucus Nigra extract;
• 5% Primulae flos cum calycibus dry extract;
• 1.5% Pelargonium sidoides dry extract;
• 3% Echinacea dry extract;
• 4% purified Propolis extract.

Example 1: Example of composition:

• 20 mg d’Argent au total à hauteur de 20% d’argent sous forme ionique et 80% d’argent sous forme colloïde, de taille de particule moyenne 0,8nm.
• 0,9% d’extrait de Sambucus Nigra
• 5% d’extrait sec Primulae flos cum calycibus
• 1,5% d’extrait sec Pélargonium sidoides.
• 3% extrait sec Echinacea
• 4% extrait purifié Propolis.

The composition includes, for 100 mL of composition:

• 20 mg of silver in total up to 20% silver in ionic form and 80% silver in colloid form, with an average particle size of 0.8 nm.
• 0.9% Sambucus Nigra extract
• 5% Primulae flos cum calycibus dry extract
• 1.5% Pelargonium sidoides dry extract.
• 3% Echinacea dry extract
• 4% purified Propolis extract.

Example 2: Antibacterial activity of the composition of example 1.

The antibacterial activity is studied by monitoring in vitro the densities of cultivable Staphylococcus aureus after inoculation of the strains tested and contact with the composition of Example 1.

The densities expressed in CFU/ml are measured for periods of 1, 3 and 24 hours, and make it possible to characterize a bactericidal effect.

The results show that the composition exhibits a bactericidal effect.

Example 3: Anti-viral effect of the composition of example 1.

The composition of Example 1 is tested according to the test for the evaluation of potential activity against HRV-A16 (a rhinovirus responsible for colds) on a culture of fully differentiated human airway epithelial cells. The compositions are first applied before infection for one hour and replication is carried out for 4 hours. 3 rinsing steps with the formulations are carried out. The rest is collected and the RNA is assayed after cell lysis. The same collection step is performed 24 hours later and the same assay step is performed. The percentage expresses the changes in viral RNA, resulting in percentage inhibition of HRV-A16 replication, leading to anti-viral efficacy. The composition according to example 1 is tested against rupintrivir (a known antiviral compound, providing an almost complete response). The results are superior for the composition according to example 1.

Example 4: Antifungal activity of the composition according to example 1:

A strain of Scytalidium dimidiatum is obtained by separation and identification of stratum corneum from patients with superficial mycosis. Fungi pre-cultivated on SDA medium are suspended in a sterile saline solution containing 0.1% (w/v) Tween 80 and the suspension is filtered through cheesecloth to collect the arthrospores. This is suspended in a sterile saline solution containing 0.1% (w/v) Tween 80, then added to a medium containing 20% Alamar blue at 2 x 104 cells/ml to give fungal inoculum solution.

The composition according to example 1 was used, as well as luliconazole.

Test method

The minimum inhibitory concentration (MIC) is measured by a broth microdilution method. That is, RPMI1640 medium (Sigma-Aldrich) was buffered with 0.165 M morpholine propanesulfonic acid (MOPS, Wako Pure Chemical Industries, Ltd.) at pH 7.0, and a given amount of a solution of the composition according to example 1 or of luliconazole is added to prepare series of double dilutions in the range of 0.00098-4 μg/mL. 100 μl are added to a 96-well microplate, then a fungal inoculum solution (100 μl, final concentration of fungi to be added: 1.0 x 104 cells/ml) and the mixture is cultured at 35°C. An Alamar blue reagent is previously added to the culture medium (final concentration of the addition: 10%) and, at the moment when the Alamar blue reagent in the growth control group without drug changes from blue to red , the culture is interrupted and the absorbance (differential optical density at 570 nm on the basis of 590 nm served as a reference) measured. The minimum concentration of the composition according to Example 1 or of luliconazole which inhibited the growth of the fungus in the growth control group by 80% or more is taken as the MIC. The concentration to be the MIC (MIC90) in 9 strains out of the 10 strains measured (90%) is determined.

Reference documents for the measurement method: Takako Shinoda and others: advice proposed by the Clinical Laboratory Standards Committee of the Japanese Society of Medical Mycology (1995 - 1997), Method for antifungal susceptibility testing of filamentous fungus, Medical Mycology Journal, 40: 239-257, 1999. Clinical Laboratory Standards Institute/National Clinical Laboratory Standards Committee. Reference method for testing the antifungal susceptibility of filamentous fungi by dilution in culture broth. Standard approved M38-A2. Wayne, PA: National Committee for Clinical Laboratory Standards, 2008.

Results

The MIC of the composition according to example 1 is higher than luliconazole, demonstrating a specifically strong antifungal activity.

Example 5: In vivo antiviral, antibacterial, antifungal efficacy test

Two groups of 20 patients each, suffering from viral, fungal and/or bacterial infection, were treated with the composition described in Example 1 or with a saline solution (PLACEBO). The treatment consisted of spraying the composition of example 1 and PLACEBO twice a day. The treatment lasted two weeks. Efficacy of treatment was assessed using a total symptom score, linked to swab samples. The scores, evaluated at the beginning and at the end of the treatment with the Student's t-test, were used to assign an efficacy score with the same statistical method.

The results demonstrated that the composition of Example 1 was more effective than the saline solution.

Claims (10)

Composition for use as a medicament comprising:

• Silver in colloidal form;
• An extract of Sambucus Nigra;
• An extract of Primulae flos cum calycibus;
• An extract of pelargonium sidoides.

Composition for use as medicine according to the preceding claim, characterized in that the said silver in colloidal form has a particle size of between 0.1 and 30 nanometers. A composition for use according to any preceding claim, comprising:

• Between 20 mg and 250 mg of silver in colloidal form per liter of composition;
• Between 0.3 and 5% by weight of the Sambucus Nigra Extract composition;
• Between 1 and 9% by weight of the composition of Primulae flos cum calycibus extract;
• Between 1 and 6% by weight of the composition of Pelargonium sidoides extract.

Composition for use according to claims 1 and 2, further comprising:

• Silver in ionic form;

Composition for use as a medicament according to the preceding claim, comprising:

• Between 20 mg and 250 mg of total silver per liter of composition, divided into
  1. Between 70 and 99.99% by total weight of silver, silver in colloidal form;
  2. Between 0.01 and 30% by total weight of silver, silver in ionic form.
• Between 0.3 and 5% by weight of the Sambucus Nigra Extract composition;
• Between 1 and 9% by weight of the composition of Primulae flos cum calycibus extract;
• Between 1 and 6% by weight of the composition of Pelargonium sidoides extract.

A composition for use according to any preceding claim, further comprising:

• An extract of Echinacea, and/or
• Propolis and/or
• An extract of Artemisia and/or
• An extract of Allium sativum.

Composition for use according to the preceding claim, comprising:

• Between 0.01 and 8% by weight of the Echinacea extract composition, and/or
• Between 0.01 and 7% by weight of the Propolis composition, and/or
• Between 0.5 and 3% by weight of the Artemisia extract composition, and/or
• Between 0.01 and 10% by weight of the Allium sativum extract composition.

A composition for use according to any preceding claim, for use in antiviral, antibacterial and antifungal prophylaxis and/or treatment. Composition for use according to any one of the preceding claims, characterized in that it is in a form suitable for administration by the oral route, by the intravenous route, by the subcutaneous route, by the nasal route, by the ophthalmic route, by the auricular route, rectally, vaginally, by the respiratory route, or by application to the skin. Composition for use according to the preceding claim, characterized in that it is in a form suitable for administration by the respiratory or nasal route, in the form of nasal drops, nasal spray, nasal powder, aerosol, for example aerosols and/or compressed gas nasal spray, or nebulizer.