# US 10,869,881 B2 · Pharmaceutical composition comprising particles comprising a complex of a double-stranded polyribonucleotide and a polyalkyleneimine

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- Number: US 10,869,881 B2
- Document ID: US10869881B2
- Status: Granted
- Kind: B2
- Application number: 16/724,519
- Filed: 2019-12-23
- Published: 2020-05-28
- Granted: 2020-12-22
- Earliest claimed: 2017-05-17
- Assignees: Highlight Therapeutics, S.L.
- Applicants: Highlight Therapeutics, SL
- Inventors: Mercedes Pozuelo Rubio; Marisol Quintero Ortiz; Ana Villanueva Garcia
- Web page: https://patentgrep.com/patent/US10869881B2

## CPC

- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- 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 9/08: Solutions {(composition of solutions A61K47/00)}
- 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 31/00: Medicinal preparations containing organic active ingredients
- A61K 31/15: Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) {; Imines (C—N=C)}
- A61K 31/74: Synthetic polymeric materials
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61K 47/50: the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K 47/59: obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K 47/6929: {the form being a nanoparticle, e.g. an immuno-nanoparticle}
- A61K 47/6935: {the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol}
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The present invention relates to compositions comprising particles, each of said particles comprising a complex of at least one double-stranded polyribonucleotide, such as polyinosinic-polycytidylic acid [poly(I:C)], and at least one linear polyalkyleneimine. The particles are also characterized by their monomodal diameter distribution and z-average diameter within specific ranges. The present invention additionally relates to use of said compositions as medicaments, in particular for the treatment of a cell growth disorder characterized by abnormal growth of human or animal cells, as well as to processes for the preparation of said compositions.

## Claims

### Claim 1

An aqueous composition comprising one or more particles, wherein
(a) each particle comprises a complex of at least one double-stranded polyribonucleotide, or a salt or solvate thereof, and at least one polyalkyleneimine, or a salt and/or solvate thereof, wherein
(i) the double-stranded polyribonucleotide is polyinosinic-polycytidylic acid [poly(I:C)], wherein
at least 60% of the double-stranded polyribonucleotides have at least 850 base pairs,
at least 70% of the double-stranded polyribonucleotides have between 400 and 5000 base pairs, and
between 20% and 45% of the double-stranded polyribonucleotides have between 400 and 850 base pairs; and
(ii) the polyalkyleneimine comprises at least 95% linear polyethyleneimines,
wherein the average molecular weight of the linear polyalkyleneimine is between 17 and 23 kDa and the polydispersity index is <1.5, and
wherein the ratio of the number of moles of nitrogen of the polyalkyleneimine to the number of moles of phosphorus of the double-stranded polyribonucleotide is between 2.5 and 5.5; and
(b) the one or more particles each have a z-average diameter measured according to ISO 22412:2008 of between 30 nm and 150 nm.

### Claim 2 (depends on 1)

The composition according to claim 1, wherein at least 99% of the one or more particles have a diameter distribution below 600 nm.

### Claim 3 (depends on 1)

The composition according to claim 1, wherein the composition has a zeta potential of between 35 and 50 mV, measured according to ISO 13099-2:2012.

### Claim 4 (depends on 1)

The composition according to claim 1, wherein the linear polyalkyleneimine is a water-soluble homo-polyalkyleneimine or a hetero-polyalkyleneimine.

### Claim 5 (depends on 1)

The composition according to claim 1, wherein the polyinosinic-polycytidylic acid [poly(I:C)] concentration is at least 0.5 mg/ml.

### Claim 6 (depends on 1)

The composition according to claim 1, wherein the composition further comprises
(a) at least one pharmaceutically acceptable carrier, organic solvent, excipient and/or adjuvant; and/or
(b) at least one compound selected from an organic compound, an inorganic compound, a nucleic acid, an aptamer, a peptide and a protein.

### Claim 7 (depends on 1)

The composition according to claim 1, further comprising glucose or mannitol at a concentration of between 1 and 10% weight/volume of the composition.

### Claim 8 (depends on 1)

The composition according to claim 1, wherein the composition further comprises:
(a) a pH of between 2 and 4; and/or
(b) an osmolarity of between 200 and 600 mOsm/kg.

### Claim 9 (depends on 1)

The composition according to claim 1, wherein the complex contains at least 0.5 mg of polyinosinic-polycytidylic acid [poly(I:C)] per ml of the total volume of the composition.

### Claim 10 (depends on 1)

The composition according to claim 1, wherein the composition further comprises glucose or mannitol in a concentration of between 1 and 10% weight/volume of the composition.

### Claim 11 (depends on 1)

The composition according to claim 1, wherein the one or more particles has a mono-modal diameter distribution.

### Claim 12 (depends on 1)

A method for manufacturing the aqueous composition according to claim 1, comprising:
(a) providing (i) a first aqueous solution of at least one double-stranded polyribonucleotide, or a salt or solvate thereof, and (ii) a second aqueous solution of at least one linear polyalkyleneimine, or a salt or solvate thereof;
(b) filtering each respective first and second aqueous solution of step (a) independently through a filter having a pore diameter of less than or equal to 500 nm to form a respective resulting sterilized solution; and
(c) mixing each respective resulting sterilized solution in a mixing chamber by simultaneous addition of each respective resulting sterilized solution into the mixing chamber, optionally by injection, at a rate of greater than or equal to 1 ml/min, to form the aqueous composition of claim 1.

### Claim 13 (depends on 12)

The method according to claim 12, further comprising:
(d) filtering the resulting aqueous composition of step (c) through a filter having a pore diameter of less than or equal to 600 nm to form a filtrate, or centrifuging the resulting aqueous composition of step (c) at greater than or equal to 22480 m/s2 to form a supernatant.

### Claim 14 (depends on 13)

The method of claim 13, further comprising:
(e) lyophilising the filtrate or supernatant of step (d).

### Claim 15 (depends on 12)

The method according to claim 12, wherein each of or both aqueous solutions of step (a) further comprise a pharmaceutically acceptable carrier, organic solvent, excipient and/or adjuvant.