Stable formulations for lyophilizing therapeutic particles

Patent metadata

Field	Value
Publication number	US-9498443-B2
Application number	US-201414535713-A
Country	US
Kind code	B2
Filing date	Nov 7, 2014
Priority date	Dec 11, 2009
Publication date	Nov 22, 2016
Grant date	Nov 22, 2016

Abstract

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

First claim

The invention claimed is:

1. A lyophilized pharmaceutical composition comprising: polymeric nanoparticles comprising: 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;
a sugar; and
hydroxypropyl β-cyclodextrin,
wherein upon reconstitution of the lyophilized pharmaceutical composition in an aqueous medium, the composition comprises 4 to 6 weight percent of the sugar; and 7 to 12 weight percent of the hydroxypropyl β-cyclodextrin.

2. The lyophilized pharmaceutical composition of claim 1 , wherein the reconstituted composition comprises:
less than 6000 microparticles having a size greater than or equal to 10 microns; and
less than 600 microparticles having a size greater than or equal to 25 microns wherein the number of microparticles is determined according to USP 32<788> light obscuration particle count test; or wherein the number of microparticles is determined according to USP 32<788> by microscopic particle count test; or wherein the number of microparticles is determined using single particle optical sensing.

3. The lyophilized pharmaceutical composition of claim 1 , wherein the reconstituted composition has a nanoparticle concentration of about 10-100 mg/mL.

4. 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.

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

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

7. The lyophilized pharmaceutical composition of claim 1 , wherein the sugar comprises a disaccharide wherein the reconstituted composition has minimal aggregation compared to a reconstituted composition that does not contain a cyclodextrin.

8. The lyophilized pharmaceutical composition of claim 7 , wherein the disaccharide is sucrose or trehalose, or a mixture thereof.

9. The lyophilized pharmaceutical composition of claim 7 , wherein the lyophilized pharmaceutical composition comprises about 1 to about 25 weight percent hydroxypropyl β-cyclodextrin.

Assignees

• Bind Therapeutics Inc
• Pfizer

Inventors

• Troiano Greg
• Song Young-Ho
• Zale Stephen E
• Wright James
• Van Geen Hoven Christina

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K9/5192

  Processes · CPC title

• A61K9/5153

  Polyesters, e.g. poly(lactide-co-glycolide) · CPC title

• C08G63/664

  derived from hydroxy carboxylic acids · CPC title

• A61K47/26

  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 · CPC title