# US 9,872,848 B2 · Stable formulations for lyophilizing therapeutic particles

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- Number: US 9,872,848 B2
- Document ID: US9872848B2
- Status: Granted
- Kind: B2
- Application number: 15/296,350
- Filed: 2016-10-18
- Published: 2017-07-06
- Granted: 2018-01-23
- Earliest claimed: 2009-12-11
- Assignees: Pfizer Inc.
- Applicants: Pfizer Inc.
- Inventors: Greg Troiano; Young-ho Song; Stephen E. Zale; James Wright; Christina Van Geen Hoven
- Web page: https://patentgrep.com/patent/US9872848B2

## CPC

- A61K 31/337: having four-membered rings, e.g. taxol
- 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 9/16: Agglomerates; Granulates; Microbeadlets {; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction (A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51)}
- 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 9/5123: {Organic compounds, e.g. fats, sugars}
- A61K 9/5153: {Polyesters, e.g. poly(lactide-co-glycolide)}
- A61K 9/5161: {Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin}
- A61K 9/5192: {Processes}
- A61K 31/335: having oxygen as the only ring hetero atom, e.g. fungichromin
- 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 47/34: 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 47/40: Cyclodextrins; Derivatives thereof
- A61P 35/00: Antineoplastic agents
- C08G 63/664: derived from hydroxy carboxylic acids
- Y10S 977/906: Drug delivery
- 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
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- Y10S: TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS

## Abstract

The present disclosure generally relates to lyophilized pharmaceutical compositions comprising polymeric nanoparticles which, upon reconstitution, have low levels of greater than 10 micron size particles. Other aspects of the invention include methods of making such nanoparticles.

## Claims

### Claim 1

A lyophilized pharmaceutical composition comprising:
polymeric nanoparticles that comprises a poly(lactic) acid-block-poly(ethylene)glycol copolymer or poly(lactic)-co-poly(glycolic) acid-block-poly(ethylene)glycol copolymer, and a therapeutic agent, wherein the polymeric nanoparticles have a diameter of about 60 nm to about 140 nm;
a sugar; and
hydroxypropyl β-cyclodextrin,
wherein upon reconstitution of the lyophilized pharmaceutical composition in an aqueous medium, the reconstituted composition comprises 10-100 mg/mL concentration of the nanoparticles; 4 to 6 weight percent of the sugar; and 7 to 12 weight percent of the hydroxypropyl β-cyclodextrin, and wherein 100 mL of the reconstituted composition comprises less than 6000 microparticles of greater than or equal to 10 microns; and less than 600 microparticles of greater than or equal to 25 microns.

### Claim 2 (depends on 1)

The lyophilized pharmaceutical composition of claim 1, wherein 100 mL of the reconstituted composition comprises:
less than 3000 microparticles having a size greater than or equal to 10 microns; and
less than 300 microparticles having a size greater than or equal to 25 microns.

### Claim 3 (depends on 1)

The lyophilized pharmaceutical composition of claim 1, wherein the polymeric nanoparticles have a diameter of about 60 nm to about 120 nm.

### Claim 4 (depends on 1)

The lyophilized pharmaceutical composition of claim 1, wherein the polymeric nanoparticles have a diameter of about 70 nm to about 130 nm.

### Claim 5 (depends on 1)

The lyophilized pharmaceutical composition of claim 1, wherein the therapeutic agent is a taxane agent.

### Claim 6 (depends on 1)

The lyophilized pharmaceutical composition of claim 1, wherein the nanoparticles comprise a poly(lactic) acid-block-poly(ethylene)glycol copolymer.

### Claim 7 (depends on 1)

The lyophilized pharmaceutical composition of claim 1, wherein the reconstituted composition has a nanoparticle concentration of about 40-60 mg/mL.

### Claim 8 (depends on 1)

The lyophilized pharmaceutical composition of claim 1, wherein the poly(lactic) acid portion of the copolymer has a weight average molecular weight of about 16 kDa and the poly(ethylene)glycol portion of the copolymer has a weight average molecular weight of about 5 kDa.

### Claim 9 (depends on 1)

The lyophilized pharmaceutical composition of claim 1, wherein the therapeutic agent is an anti-cancer agent.

### Claim 10 (depends on 1)

The lyophilized pharmaceutical composition of claim 1, wherein the therapeutic agent is docetaxel.

### Claim 11 (depends on 1)

The lyophilized pharmaceutical composition of claim 1, wherein the sugar comprises a disaccharide.

### Claim 12 (depends on 11)

The lyophilized pharmaceutical composition of claim 11, wherein the disaccharide is sucrose or trehalose, or a mixture thereof.

### Claim 13 (depends on 12)

The lyophilized pharmaceutical composition of claim 12, wherein the disaccharide is sucrose.

### Claim 14 (depends on 11)

The lyophilized pharmaceutical composition of- claim 11, wherein the disaccharide is trehalose.

### Claim 15 (depends on 11)

The lyophilized pharmaceutical composition of claim 11, wherein the reconstituted composition comprises about 5 weight percent of disaccharide and about 10 weight percent hydrxoypropyl β-cyclodextrin.

### Claim 16 (depends on 11)

The lyophilized pharmaceutical composition of claim 11, wherein the reconstituted composition has minimal aggregation compared to a reconstituted composition that does not contain a cyclodextrin.

### Claim 17 (depends on 1)

The lyophilized pharmaceutical composition of claim 1, wherein the reconstituted composition has a polydispersity index of less than 0.2.