# US 10,765,753 B2 · Polymer nanoparticle freeze-dried product, and preparation method therefor

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- Number: US 10,765,753 B2
- Document ID: US10765753B2
- Status: Granted
- Kind: B2
- Application number: 15/540,674
- Filed: 2015-12-28
- Published: 2018-01-04
- Granted: 2020-09-08
- Earliest claimed: 2014-12-30
- Assignees: Samyang Biopharmaceuticals Corporation
- Applicants: Samyang Biopharmaceuticals Corporation
- Inventors: Sa Won Lee; Gyeong Hae Kim; Min Hyo Seo
- Web page: https://patentgrep.com/patent/US10765753B2

## CPC

- A61K 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence)
- 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 9/5146: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides}
- A61K 9/5153: {Polyesters, e.g. poly(lactide-co-glycolide)}
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/506: not condensed and containing further heterocyclic rings
- 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
- C08G 63/06: derived from hydroxycarboxylic acids
- C08K 3/10: Metal compounds
- C08K 2003/162: {Calcium, strontium or barium halides, e.g. calcium, strontium or barium chloride}
- C08K 2003/2206: {of calcium, strontium or barium}
- 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)
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08K: Use of inorganic or non-macromolecular organic substances as compounding ingredients (paints, inks, varnishes, dyes, polishes, adhesives C09)

## Abstract

The present invention relates to a polymer nanoparticle freeze-dried product, and a preparation method therefor, the polymer nanoparticle freeze-dried product being obtainable by treating, through a freeze-drying process comprising an annealing step, a polymer nanoparticle aqueous solution comprising an amphiphilic block copolymer, a polylactic acid derivative having a carboxyl terminal group, and a freeze-drying adjuvant, wherein the polymer nanoparticle freeze-dried product is reconstituted within five minutes upon reconstitution by means of an aqueous solvent under atmospheric pressure.

## Claims

### Claim 1

A method for preparing lyophilizate of polymeric nanoparticle by lyophilization process of a solution of polymeric nanoparticle,
wherein the solution of polymeric nanoparticle comprises an amphiphilic block copolymer consisting of a hydrophilic block (A) and a hydrophobic block (B) in A-B, A-B-A or B-A-B form; a polylactic acid derivative having carboxyl terminal group; a lyophilization aid; and a poorly water-soluble drug which is paclitaxel or docetaxel,
wherein the solution of polymeric nanoparticle has a polymer concentration of 120 mg/ml or lower,
wherein the lyophilization process comprises:
a) a first freezing step where the solution of polymeric nanoparticle is frozen to a temperature in the range of −10 to −45° C.;
b) an annealing step where the resulting product of the first freezing is heated to a temperature in the range of −25 to 0° C.;
c) a second freezing step where the resulting product of the annealing is frozen to a temperature in the range of −10 to −45° C.;
d) a primary drying step where the resulting product of the second freezing is dried at a temperature of lower than 0° C. under reduced pressure;
e) a secondary drying step where the resulting product of the primary drying is dried at a temperature of 0° C. or higher under reduced pressure; and
f) introducing the resulting product into a vial, and sealing the vial in vacuo; and
wherein the lyophilizate of polymeric nanoparticle is reconstituted within 5 minutes when reconstituted with an aqueous solvent under atmospheric pressure;
the amount of the lyophilization aid is 10 to 60% by weight, based on the total dry weight of the lyophilizate of polymeric nanoparticle;
the hydrophilic block (A) is selected from the group consisting of polyethylene glycol, monomethoxypolyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol and polyacrylamide; and the hydrophobic block (B) is selected from the group consisting of polylactide, polyglycolide, polydioxan-2-one, polycaprolactone, polylactic-co-glycolide, polylactic-co-caprolactone, polylactic-co-dioxan-2-one and polyglycolic-co-caprolactone;
the hydrophilic block (A) has a number average molecular weight of 500 to 50,000 Daltons; and the hydrophobic block (B) has a number average molecular weight of 500 to 50,000 Daltons;
the polylactic acid derivative having carboxyl terminal group has a number average molecular weight of 500 to 5,000 Daltons; and
the lyophilizate has an average pore size of 70 μm or greater.

### Claim 2 (depends on 1)

The method for preparing lyophilizate of polymeric nanoparticle according to claim 1, wherein, in the lyophilization process,
the first freezing is conducted from an initial temperature of 0 to 35° C. to a final temperature of −10 to −45° C. with reducing the temperature for 0.5 to 24 hours followed by maintaining the temperature for 0.5 to 24 hours;
the annealing is conducted from an initial temperature of −10 to −45° C. to a final temperature of −25 to 0° C. with elevating the temperature for 0.5 to 24 hours followed by maintaining the temperature for 0.2 to 12 hours;
the second freezing is conducted from an initial temperature of −25 to 0° C. to a final temperature of −10 to −45° C. with reducing the temperature for 0.5 to 24 hours followed by maintaining the temperature for 0.5 to 24 hours;
the primary drying is conducted under a vacuum degree of 50 to 500 mTorr at a temperature of −45 to below 0° C. for 24 to 96 hours; and
the secondary drying is conducted under a vacuum degree of 50 to 500 mTorr at a temperature of 0 to 50° C. for 6 to 48 hours.

### Claim 3 (depends on 1)

The method for preparing lyophilizate of polymeric nanoparticle according to claim 1, wherein the hydrophilic block (A) has a number average molecular weight of 500 to 20,000 Daltons; and the hydrophobic block (B) has a number average molecular weight of 500 to 20,000 Daltons.

### Claim 4 (depends on 3)

The method for preparing lyophilizate of polymeric nanoparticle according to claim 3, wherein the weight ratio of the hydrophilic block (A): the hydrophobic block (B) in the amphiphilic block copolymer is 2:8 to 8:2.

### Claim 5 (depends on 1)

The method for preparing lyophilizate of polymeric nanoparticle according to claim 1, wherein the polylactic acid derivative having carboxyl terminal group is one having alkali metal ion bonded to the terminal carboxylic acid group or carboxyl group of one or more selected from the group consisting of D,L-polylactic acid, D-polylactic acid, polymandelic acid, copolymer of D,L-lactic acid and glycolic acid, copolymer of D,L-lactic acid and mandelic acid, copolymer of D,L-lactic acid and caprolactone, and copolymer of D,L-lactic acid and 1,4-dioxan-2-one.

### Claim 6 (depends on 1)

The method for preparing lyophilizate of polymeric nanoparticle according to claim 1, wherein the solution of polymeric nanoparticle further comprises salt of divalent or trivalent metal ion.

### Claim 7 (depends on 6)

The method for preparing lyophilizate of polymeric nanoparticle according to claim 6, wherein the divalent or trivalent metal ion is selected from the group consisting of calcium (Ca2+), magnesium (Mg2+), barium (Ba2+), chromium (Cr3+), iron (Fe3+), manganese (Mn2+), nickel (Ni5+), copper (Cu2+), zinc (Zn2+) and aluminum (Al3+).

### Claim 8 (depends on 1)

The method for preparing lyophilizate of polymeric nanoparticle according to claim 1, wherein the lyophilization aid is selected from the group consisting of sugar, sugar alcohol, and mixtures thereof.

### Claim 9 (depends on 8)

The method for preparing lyophilizate of polymeric nanoparticle according to claim 8, wherein the sugar is one or more selected from the group consisting of lactose, maltose, sucrose and trehalose; and the sugar alcohol is one or more selected from the group consisting of mannitol, sorbitol, maltitol, xylitol and lactitol.

### Claim 10 (depends on 1)

The method for preparing lyophilizate of polymeric nanoparticle according to claim 1, wherein the prepared lyophilizate of polymeric nanoparticle comprises: 0.1 to 78.9% by weight of amphiphilic block copolymer; 20.0 to 98.8% by weight of polylactic acid derivative having carboxyl terminal group bonded to divalent or trivalent metal ion; and 0.1 to 20.0% by weight of poorly water-soluble drug.