EP-4739281-A1 - AQUEOUS COMPOSITION COMPRISING AVERMECTINS

EP4739281A1EP 4739281 A1EP4739281 A1EP 4739281A1EP-4739281-A1

Abstract

An aqueous composition is provided which comprises at least one surface modifier selected from a group consisting of cellulose derivatives, in particular hydroxypropylmethyl cellulose, methylcellulose and hydroxypropylcellulose, polyvinylpyrrolidones and derivatives thereof, alginates, carrageenan, collagens, polyoxyethylene-polyoxypropylene copolymers, polyalkylene glycols, lecithins, phospholipids, pegylated phospholipids, gelatine, cholesterol, casein, tragacanth, pectins, gums, especially gum arabic, dextran, polyoxyethylen stearates, polyvinyl alcohol, polyethylene glycols, triethanolamine, tocopherol-polyethylene glycols and combinations thereof in an amount from 0.05% by weight to 15% by weight, based on the total weight of the composition, at least one active pharmaceutical ingredient selected from the group of avermectins in an amount from 2% by weight to 15% by weight, based on the total weight of the composition, having a mean particle size of 0.01 µm to 20 µm, and water in an amount from 70% by weight to 97.9% by weight, based on the total weight of the composition. Preferably, the at least one active pharmaceutical ingredient selected from the group of avermectins is ivermectin. Further, the aqueous composition is preferably for use in a pharmaceutical composition or medicament, wherein preferably for the use in the prevention or treatment of viral diseases, in particular for use in the prevention or treatment of a SARS-Covid-2 infection or of a HIV infection.

Inventors

Wissel, Stefan
RISCHER, MATTHIAS
Wissel, Philipp
Häberlein, Felix

Assignees

HWI pharma services GmbH

Dates

Publication Date: 20260513
Application Date: 20240620

Claims (1)

Claims 1. Aqueous composition comprising - at least one surface modifier selected from a group consisting of cellulose derivatives, in particular hydroxypropylmethyl cellulose, methylcellulose and hydroxypropylcellulose, polyvinylpyrrolidones and derivatives thereof, alginates, carrageenan, collagens, polyoxyethylene-polyoxypropylene copolymers, polyalkylene glycols, lecithins, phospholipids, pegylated phospholipids, gelatine, cholesterol, casein, tragacanth, pectins, gums, especially gum arabic, dextran, polyoxyethylen stearates, polyvinyl alcohol, polyethylene glycols, triethanolamine, tocopherol-polyethylene glycols and combinations thereof in an amount from 0.05% by weight to 15% by weight, based on the total weight of the composition, - at least one active pharmaceutical ingredient selected from the group of avermectins in an amount from 2% by weight to 15% by weight, based on the total weight of the composition, having a mean particle size of 0.01 pm to 20 pm obtained by laser diffraction, - water in an amount from 70% by weight to 97.9% by weight, based on the total weight of the composition, and - one surfactant, - wherein the aqueous composition is free of a second, in particular free of more than one surfactant. 2. Aqueous composition according to claim 1 , wherein the at least one surface modifier is present in the composition in an amount from 0.05% by weight to 10% by weight, preferably from 0.1 % by weight to 10% by weight, more preferably in an amount from 0.1% by weight to 8% by weight, based on the total weight of the composition. 3. Aqueous composition according to claim 1 or claim 2, wherein the at least one surface modifier is selected from a group consisting of alginate, phospholipid, polyvinylalcohol, polyvinylpyrrolidone, tocopherol-polyethylene glycols (TPGS), hydroxypropylmethyl cellulose (HPMC), dextran and combinations thereof. 4. Aqueous composition according to anyone of the preceding claims, wherein the at least one active pharmaceutical ingredient selected from the group of avermectins is ivermectin. 5. Aqueous composition according to anyone of the preceding claims, in particular according to claim 4, wherein the at least one active pharmaceutical ingredient selected from the group of avermectins is present in the composition in an amount from 2% by weight to 12% by weight, preferably from 2% by weight to 10% by weight, more preferably in an amount from 2% by weight to 8% by weight, based on the total weight of the composition. 6. Aqueous composition according to anyone of the preceding claims, wherein the at least one active pharmaceutical ingredient has a mean particle size of less than 0.5 pm, in particular from 0.1 pm to 0.5 pm and/or the at least one active pharmaceutical ingredient has a mean particle size of less than 10 pm, in particular from 1 pm to 5 pm, wherein a mean particle size from 1 pm to 3 pm is even further preferred. 7. Aqueous composition according to anyone of the preceding claims, wherein the aqueous composition further comprises at least one buffer, wherein preferably the at least one buffer is present in an amount from 0.001 % by weight to 10% by weight, preferably from 0.1% by weight to 8% by weight, more preferably from 0.14% by weight to 6% by weight, based on the total weight of the composition. 8. Aqueous composition according to claim 7, wherein the at least one buffer comprises a salt selected from a group of inorganic salts consisting of monosodium phosphate, disodium phosphate, sodium bicarbonate, dicalcium phosphate, tris(hydroxymethyl) aminomethane (TRIS), sodium citrate and sodium acetate and/or from a group of organic compounds consisting of glycine, gluconic acid and chelating agents, in particular ethylenediaminetetraacetic acid (EDTA). 9. Aqueous composition according to anyone of the preceding claims, wherein the one surfactant is selected from a group of ionic surfactants, consisting of sodium taurocholate (STC), sodium glycocholate (SGC), dioctyl sulfosuccinate ester (DOSS) and sodium dodecyl sulphate (SDS) or from a group of non-ionic surfactants consisting of polysorbate esters in an amount from 0.1 % by weight to 5 % by weight, based on the total weight of the composition. 0. Aqueous composition according to anyone of the preceding claims, wherein - the at least one surface modifier is alginate in an amount from 0.05% by weight to 1 .5% by weight, based on the total weight of the composition, - the at least one active pharmaceutical ingredient selected from the group of avermectins is ivermectin, present in an amount from 2% by weight to 8% by weight, based on the total weight of the composition, - ivermectin has a mean particle size from 0.01 pm to 10 pm, - the one surfactant present in the aqueous composition is polyoxyethylene-sorbitan- monooleat (Tween® 80), present in an amount 0.1% by weight to 0.5% by weight, based on the total weight of the composition, and - water is present in an amount from 90% by weight to 97.9% by weight, based on the total weight of the composition. 11. Aqueous composition according to claim 10, wherein a buffer is present in the aqueous composition in an amount from 0,14% by weight to 6% by weight, based on the total weight of the composition and comprises sodium citrate. 12. Aqueous composition according to anyone of the preceding claims, wherein said aqueous composition is provided for nasal application, in particular in the form of a nasal spray. 13. Discharging device, in particular a syringe or a spray device, wherein the discharging device is filled with the aqueous composition according to any one of claims 1 to 11 . 14. Aqueous composition according to any one of claims 1 to 11 , for use in a pharmaceutical composition or medicament, preferably for the use in the prevention or treatment of disorders or diseases via nasal administration, in particular for the prevention or treatment of viral diseases. 15. Aqueous composition according to any one of claims 1 to 12, for use according to claim 14 in the prevention or treatment of a SARS-Covid-2 infection.

Description

Aqueous composition comprising avermectins TECHNICAL FIELD AND PRIOR ART The present invention relates to a novel aqueous composition comprising avermectins in particular for nasal applications. The present invention also relates to a discharging device comprising this aqueous composition and to the use of this aqueous composition in a pharmaceutical composition or medicament. Further this system of aqueous composition and discharging device is particular useful in the treatment of viral diseases via a nasal application. Avermectins have been found to be active against the SARS-Covid 2 virus. However, avermectins have a low solubility in aqueous systems and are sensitive to oxidation which may lead to impurities and by-products. To prevent oxidation oral dosage forms of avermectin often comprise strong oxidation inhibitors like Butylhydroxytoluol (Driponin® 3mg) or Butylhydroxyanisol (Scabioral®). However, these oxidation inhibitors show a low solubility in aqueous systems as well. In addition to the low solubility and high oxidation sensitivity, avermectins possess a low permeability through organic tissue which impairs the release profile and bioavailability of avermectins. To improve the bioavailability of avermectins the application of a highly concentrated avermectin medication can be a solution. However, a high concentration of avermectins in an aqueous composition is nearly impossible to facilitate. Therefore, an aqueous composition of avermectins cannot facilitate an acceptable solubility of avermectins and oxidation inhibitors in an aqueous composition for medical use and a suitable concentration of avermectins which is needed to assure a good bioavailability. The use of surface modifiers and ionic surfactants has been described in detail already in US 5,298,262 A for the stabilisation of active pharmaceutical compounds in the form of nanoparticles. However, no avermectins have been used and also no intranasal applications have been described which need a careful and different design with regard to viscosity, mucoadhesion and applicability of such systems. The use of surface modifiers has been also described in US 2010/316725 A1. However, this publication is related to meloxicam nanoparticulate formulations intended for an injectable composition. US 2023/0028307 A1 is describing a method for treating a neurological disorder comprising the administration of a composition with an effective amount of avermectins to a subject in need of such treatment, but no SARS-Covid-2 treatment has been described nor any compositions for a nasal application. US 2023/0085607 A is describing a method of augmenting the prophylactic and/or therapeutic effects of ivermectin on COVID-19 when administering ivermectin together with one or more natural ingredient. However, no single administration or specific nasal application is described. US 2023/0087473 A describes the use of an anthelmintic drug like ivermectin and essential oil(s) in the form of a suspo-emulsion for naso-pulmonary use. However, no aqueous compositions are disclosed. It is an object of the present invention to provide a novel aqueous composition comprising avermectins, which has superior properties with regard to solubility, stability and bioavailability of avermectins, compared to conventional compositions comprising avermectins, preferably suitable for a nasal administration. SUMMARY OF THE INVENTION The above object and further objects are solved by an aqueous composition comprising avermectins according to claim 1 , a discharging device according to claim 13 and an aqueous composition for use in a pharmaceutical composition or medicament according to claim 14 and claim 15. Preferred embodiments are defined in the dependent claims. Preferably, but not necessarily, said aqueous composition is especially suitable for a nasal administration. The wording of all claims is explicitly incorporated into the content of this description by reference. The present invention provides an aqueous composition comprising or consisting of - at least one surface modifier selected from a group consisting of cellulose derivatives, in particular hydroxypropylmethyl cellulose, methylcellulose and hydroxypropylcellulose, polyvinylpyrrolidones and derivatives thereof, alginates, carrageenan, collagens, polyoxyethylene-polyoxypropylene copolymers, polyalkylene glycols, lecithins, phospholipids, pegylated phospholipids, gelatine, cholesterol, casein, tragacanth, pectins, gums, especially gum arabic, dextran, polyoxyethylen stearates, polyvinyl alcohol, polyethylene glycols, triethanolamine, tocopherol-polyethylene glycols and combinations thereof in an amount from 0.05% by weight to 15% by weight, based on the total weight of the composition, - at least one active pharmaceutical ingredient selected from the group of avermectins in an amount from 2% by weight to 15% by weight, based on the total weight of the composition, having a mean particle size of 0.01 pm to 20 pm, and