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EP-4225277-B1 - MESOPOROUS NANOPARTICLE SYSTEM TO INCREASE THE BIOFILM ERADICATION ACTIVITY BY MEANS OF THE CARRYING AND THE ADMINISTRATION OF AT LEAST ONE ACTIVE INGREDIENT AND RELATED PRODUCTION METHOD

EP4225277B1EP 4225277 B1EP4225277 B1EP 4225277B1EP-4225277-B1

Inventors

  • AMBROSI, Emmanuele Kizito
  • LEONETTI, Benedetta
  • CASTELLIN, ANDREA
  • SPONCHIA, Gabriele

Dates

Publication Date
20260513
Application Date
20211007

Claims (14)

  1. A system for the administration and delivery of at least one active principle for the eradication of an infection or contamination, wherein said infection or contamination is caused by a bacterial biofilm, comprising: - a vector or carrier selected from the mesoporous nanoparticles comprising pores; - at least one active principle or pharmacologically active ingredient (API) loaded into said pores of said vector and/or supported by and/or adsorbed in said vector; wherein said vector is constituted by mesoporous zirconia nanoparticles (MZNs), wherein said zirconia of said MZNs has high affinity with phosphate groups whereby said MZNs interact directly with the bacterial cell wall of said biofilm and wherein said API includes N-acetyl-L-cysteine (NAC).
  2. System according to claim 1, wherein NAC is combined with least one other active principle or pharmacologically active ingredient (API) selected from the group of molecules with antimicrobial and/or antibacterial and/or mucolytic and/or anti-inflammatory activity, more specifically comprising at least one antibiotic, vancomycin, nitrofurantoin.
  3. System according to claim 1, wherein said nanoparticles have a substantially spherical and/or spheroidal and/or irregular shape and/or an average surface area comprised in a range between 100 and 500 m 2 /g, between 150 and 250 m 2 /g, or between 190 and 230 m 2 /g and/or an average diameter in the range between 100 and 600 nm, or between 100 and 500 nm, or between 200 and 400 nm or between 200 and 300 nm or between 150 and 350 nm.
  4. System according to any one of the preceding claims, wherein said system has a load capacity of said at least one active principle or pharmacologically active ingredient (API) in said mesoporous zirconia nanoparticles comprised between 5 and 20% (weight/weight).
  5. System according to any one of the preceding claims, wherein said vector or carrier has an internal structure and an external surface and said pores are present in said internal structure and/or on said external surface and/or wherein said pores have a diameter between 2 and 50 nm, between 2 nm and 10 nm or between 4 nm and 6 nm and/or wherein said pores have an average volume substantially comprised in a range from 0.2 to 0.4 cm 3 /g, or between 0.25 and 0.35 cm 3 /g.
  6. System according to claim 5, wherein said MZNs have a positive ZP under acidic conditions at low pH values, for example of 25-30 mV, and have isoelectric point falling within the range of pH 6.0 to 7.0.
  7. System according to claim 2, comprising two or more active principles or pharmacologically active ingredients (API) different from each other, and wherein each active principle or pharmacologically active ingredient (API) is loaded in one or more mesoporous nanoparticles different from the nanoparticle or nanoparticles into which the other active principle(s) or pharmacologically active ingredient(s) (API) is loaded or are loaded.
  8. System according to claim 7, wherein vancomycin or nitrofurantoin is loaded and/or supported in one or more first mesoporous nanoparticles, while N-acetyl-L-cysteine (NAC) is loaded and/or supported in other or second mesoporous nanoparticles different from the first.
  9. Method for the production of a system for the delivery and administration of at least one active principle for the eradication of an infection or contamination, wherein said infection or contamination is caused by bacterial biofilm according to one or more of the preceding claims, comprising: a step of providing mesoporous zirconia nanoparticles (MZNs), wherein said zirconia of said MZNs has high affinity with phosphate groups whereby said MZNs interact directly with the bacterial cell wall of said biofilm, and a step of providing at least one active principle or pharmacologically active ingredient (API) and wherein said API includes N-acetyl-L-cysteine (NAC), a step of impregnation of said mesoporous zirconia nanoparticles (MZNs) by dispersing a predetermined quantity of said MZNs in water or organic solvent containing a predetermined quantity of said at least one active principle or pharmacologically active ingredient (API) with the formation of a suspension, subsequent mixing of the suspension with consequent loading of said at least one active principle or pharmacologically active ingredient (API) into the pores of said mesoporous zirconia nanoparticles (MZNs) and/or support and/or adsorption of said at least one active principle or pharmacologically active ingredient (API) in said mesoporous zirconia nanoparticles (MZNs) and, a step of separating said nanoparticles loaded with said at least one active principle or pharmacologically active ingredient (API) by means of centrifugation or filtration.
  10. Method according to claim 9, wherein said NAC is combined with at least one active principle or pharmacologically active ingredient (API) selected from the group of molecules with antimicrobial and/or antibacterial and/or mucolytic and/or anti-inflammatory activity, more specifically comprising at least one antibiotic, vancomycin, nitrofurantoin.
  11. Method according to claim 9 or 10, wherein said loading step provides for the insertion of said at least one active principle or pharmacologically active ingredient (API) in said pores of said mesoporous zirconia nanoparticles (MZNs) and/or the adsorption of said at least one active principle or pharmacologically active ingredient (API) in said mesoporous zirconia nanoparticles (MZNs) and/or on the external surface of said mesoporous zirconia nanoparticles (MZNs).
  12. Method according to any one of claims 9 to 11, wherein said loading step has a loading capacity of said at least one active principle or pharmacologically active ingredient (API) in said mesoporous zirconia nanoparticles comprised between 5 and 20% (weight/weight).
  13. System according to one or more of claims 1 to 8, for use in the eradication of an infection or contamination, wherein said infection or contamination is caused by a bacterial biofilm.
  14. System for use according to claim 13, wherein the antibiofilm activity specifically of eradication is enhanced by the loading and/or supporting process of said at least one active principle or pharmacologically active ingredient (API) via said mesoporous zirconia nanoparticles and by the vehicle of said at least one active principle or pharmacologically active ingredient (API) through said mesoporous zirconia nanoparticles in proximity and/or near and/or inside said biofilm.

Description

FIELD OF APPLICATION The present invention is part of the technical sector of systems for the administration of substances inside the human body and has particularly as its object a system of nanoparticles for the administration and delivery of at least one active principle, generally known as DDS or drug delivery systems. Specifically, the invention relates to the use of a carrier which carries at least one active principle such as for example a substance having an antimicrobial and/or antibacterial and/or mucolytic nature for the eradication of biofilms, for example of bacterial origin. TECHNICAL BACKGROUND The methods for administering pharmaceutically and pharmacologically active ingredients show a wide variability in terms of technology and application, depending on some chemical and physical characteristics of the latter, such as solubility and permeability. It is known that the most common methods of drug administration are by mouth or by injection. Lipophilic molecules represent a relatively difficult challenge in achieving systemic circulation. It is also known that these molecules belong, according to the Biopharmaceutical Classification System (BCS), to the second class (II), having low solubility and consequently low bioavailability (Advance Pharmaceutical Journal 2017; 2(6): 204-209). In another context of the state of the art, it is known that microorganisms, primarily bacteria but also fungi, have a form of innate self-defense due to the formation of niches, called biofilms, which represent the most common condition of life, compared to the free or planktonic form (Pharmaceutics 2018, 10, 279). The aforementioned biofilms are in fact consortia of microorganisms generally adhering to a biotic or abiotic surface, surrounded by a mucilaginous matrix that they self-produce. It is known that in this state, biofilms are more resistant to external attacks than cells in planktonic form. Firstly, this is due to the presence of the matrix, an aqueous gel of exopolysaccharides, proteins and extracellular DNA that hinders the diffusion of molecules inside, secondly to the release of enzymes that degrade antibiotic molecules or to efflux pumps that extrude substances. Furthermore, bacteria can live in a quiescent form such as persisters or small colony variants, with slowed metabolism. From this it follows that conventional methods of treating biofilm-associated infections involve intensive administration of antibiotics, therefore high doses and for prolonged times. This generates numerous adverse effects, including emergence of antibiotic resistance and superbugs, adverse effects on the microbiome, or hypersensitivity. These issues have led research to focus on alternative therapies to antibiotics, including bacteriophages, antimicrobial peptides, specific molecules that target structures within biofilms or that interfere with quorum sensing, i.e., the process that regulates communication between cells and which appears to be fundamental for the formation of the aforementioned structures such as biofilms. In this context of innovation also nanotechnologies are inserted, structures of which at least one of the dimensions is of the order of nanometres and which, precisely because of the aforementioned dimensions, have peculiar characteristics different from the bulk counterpart of the same materials that constitute them. Some nanoparticles (NPs) are studied precisely to have antibacterial characteristics, interacting with the bacterial membrane or wall, or generating reactive oxygen species or other nanostructures are able to deliver antibacterial drugs to the site of infection. In this context, among the inorganic materials (Pharmaceutics 2018, 10, 279), mesoporous silica nanoparticles (MSN) emerge, known for their stability, high surface area and high pore volume, which give them high loading capacity of molecules of different types. For this reason, the most recent studies have focused on the search for carriers that can overcome the aforementioned limit in the bioavailability of the so-called pharmaceutically active ingredients (API - Active Pharmaceutical Ingredients) (Nature Materials 2013 12: 991-1003; Expert Opinion on Drug Delivery 2016, 13(1): 93-108). In this sense, the vehicle and drug delivery systems (DDS - Drug Delivery Systems) with a nanometric structure have aroused great interest as they provide large surface areas available for the adsorption of APIs. Furthermore, they are versatile systems that allow multiple surface modifications to allow a more effective control of the release conditions for the molecules of interest. Among the various solutions proposed, mesoporous inorganic materials have aroused particular interest, which have proved to be effective as API carriers. Recent studies have focused in particular on the composition of mesoporous materials and on the main advantages deriving from mesoporous carriers based on the variation of structural parameters such as size, surface ar