# US 2023/0056857 A1 · Nanosystems for controlled transport of active molecules for diagnostic, prognostic and therapeutic purposes

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- Number: US 2023/0056857 A1
- Document ID: US20230056857A1
- Status: Published application
- Kind: A1
- Application number: 17/976,076
- Filed: 2022-10-28
- Published: 2023-02-23
- Earliest claimed: 2015-12-21
- Assignees: Fidia Farmaceutici S.P.A.; Nanogetic S.L.
- Applicants: Fidia Farmaceutici S.P.A.; Nanogetic S.L.
- Inventors: Rosario Maria SANCHEZ MARTIN; Salvatore PERNAGALLO; Juan Diego UNCITI BROCETA; Luciano MESSINA; Susanna VACCARO; Laura PILOTTO
- Web page: https://patentgrep.com/patent/US20230056857A1

## CPC

- A61K 47/6933: {the polymer being obtained by reactions only involving carbon to carbon, e.g. poly(meth)acrylate, polystyrene, polyvinylpyrrolidone or polyvinylalcohol}
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 38/446: {Superoxide dismutase (1.15)}
- A61K 38/47: acting on glycosyl compounds (3.2), e.g. cellulases, lactases
- A61K 38/4886: {Metalloendopeptidases (3.4.24), e.g. collagenase}
- A61K 47/6937: {the polymer being PLGA, PLA or polyglycolic acid}
- A61K 47/6939: {the polymer being a polysaccharide, e.g. starch, chitosan, chitin, cellulose or pectin}
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0073: {Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; (nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M)}
- A61K 9/10: Dispersions; Emulsions
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Disclosed is a nanoparticle system consisting of a polymer support or substrate in the form of nanoparticles to which a hydrolase enzyme able to degrade hyaluronic acid and one or more biologically and/or pharmacologically active molecules are covalently bonded, its preparation process and its uses in the diagnostic, prognostic and therapeutic fields.

## Claims

### Claim 1

A nanoparticle system, comprising:
polystyrene nanoparticles wherein the nanoparticles are 200 nm in size and covalently bonded to a heterocarbon chain; and
a hyaluronidase;
wherein the polystyrene nanoparticles covalently bonded to a heterocarbon chain are formed by reacting amino-functionalized polystyrene nanoparticles with N-Fmoc-N″-succinyl-4,7,10-trioxa-1,13-tridecanediamine to covalently bond primary amines on the polystyrene to functional groups on the heterocarbon chain;
wherein the hyaluronidase is recombinant hyaluronidase rHyal_Sk; and
wherein the recombinant hyaluronidase rHyal_Sk is bonded to the heterocarbon chain via diethyl squarate.

### Claim 2 (depends on 1)

A pharmaceutical composition comprising the nanoparticle system of claim 1 in admixture with pharmaceutically acceptable excipients.

### Claim 3 (depends on 2)

The pharmaceutical composition according to claim 2 in lyophilized form for reconstitution, in aqueous suspension, or in gel form.

### Claim 4 (depends on 2)

The pharmaceutical composition according to claim 2 for subcutaneous, intradermal, intrathecal, intramuscular, intraperitoneal, intravenous, intra-arterial, transdermal, transcutaneous, transmucosal or inhalatory administration.

### Claim 5

A nanoparticle system, comprising:
polystyrene nanoparticles, wherein the nanoparticles are 200 nm in size and covalently bonded to a heterocarbon chain; and
a hyaluronidase;
wherein the polystyrene nanoparticles covalently bonded to a heterocarbon chain are formed by reacting amino-functionalized polystyrene nanoparticles with N-Fmoc-N″-succinyl-4,7,10-trioxa-1,13-tridecanediamine to covalently bond primary amines on the polystyrene to functional groups on the heterocarbon chain;
wherein the hyaluronidase is recombinant hyaluronidase rHyal_Sk;
wherein the recombinant hyaluronidase rHyal_Sk is bonded to the heterocarbon chain via diethyl squarate; and
wherein the heterocarbon chain does not contain a free charge.

### Claim 6 (depends on 5)

A pharmaceutical composition comprising the nanoparticle system of claim 5 in admixture with pharmaceutically acceptable excipients.

### Claim 7 (depends on 6)

The pharmaceutical composition according to claim 6 in lyophilized form for reconstitution, in aqueous suspension, or in gel form.

### Claim 8 (depends on 6)

The pharmaceutical composition according to claim 6 for subcutaneous, intradermal, intrathecal, intramuscular, intraperitoneal, intravenous, intra-arterial, transdermal, transcutaneous, transmucosal or inhalatory administration.

### Claim 9 (depends on 1)

A process for the preparation of the nanoparticle system according to claim 1, comprising:
a) functionalizing polystyrene nanoparticles with amino groups to obtain amino-functionalized polystyrene nanoparticles;
b) reacting the amino-functionalized polystyrene nanoparticles from step a) with N-Fmoc-N″-succinyl-4,7,10-trioxa-1,13-tridecanediamine in the presence of an activating agent to obtain nanoparticles with a protecting Fmoc group;
c) removing the protecting Fmoc group from the nanoparticles from step b);
d) reacting the nanoparticles from step c) with diethylsquarate in N,N-diisopropylethylamine and ethanol; and
e) functionalizing the nanoparticles from step d) with recombinant hyaluronidase type rHyal_Sk in a reaction medium with pH values ranging between 7 and 11.

### Claim 10 (depends on 9)

The process according to claim 9, wherein:
step b) is carried out in dimethylformamide;
the activating agent in step b) is N,N′-diisopropylcarbodiimide;
the removal of the Fmoc group in step c) is carried out by treatment with a 20% piperidine solution in dimethylformamide; and
the reaction medium in step e) is a sodium borate solution at pH 10 by addition of 1N NaOH.