title: A novel in situ hydrophobic ion paring (HIP) formulation strategy for clinical product selection of a nanoparticle drug delivery system.
abstract: The present studies were aimed at formulating AZD2811-loaded polylactic acid-polyethylene glycol (PLA-PEG) nanoparticles with adjustable release rates without altering the chemical structures of the polymer or active pharmaceutical ingredient (API). This was accomplished through the use of a hydrophobic ion pairing approach. A series of AZD2811-containing nanoparticles with a variety of hydrophobic counterions including oleic acid, 1-hydroxy-2-naphthoic acid, cholic acid, deoxycholic acid, dioctylsulfosuccinic acid, and pamoic acid is described. The hydrophobicity of AZD2811 was increased through formation of ion pairs with these hydrophobic counterions, producing nanoparticles with exceptionally high drug loading-up to five fold higher encapsulation efficiency and drug loading compared to nanoparticles made without hydrophobic ion pairs. Furthermore, the rate at which the drug was released from the nanoparticles could be controlled by employing counterions with various hydrophobicities and structures, resulting in release half-lives ranging from about 2 to 120h using the same polymer, nanoparticle size, and nanoemulsion process. Process recipe variables affecting drug load and release rate were identified, including pH and molarity of quench buffer. Ion pair formation between AZD2811 and pamoic acid as a model counterion was investigated using solubility enhancement as well as nuclear magnetic resonance spectroscopy to demonstrate solution-state interactions. Further evidence for an ion pairing mechanism of controlled release was provided through the measurement of API and counterion release profiles using high-performance liquid chromatography, which had stoichiometric relationships. Finally, Raman spectra of an AZD2811-pamoate salt compared well with those of the formulated nanoparticles, while single components (AZD2811, pamoic acid) alone did not. A library of AZD2811 batches was created for analytical and preclinical characterization. Dramatically improved preclinical efficacy and tolerability data were generated for the pamoic acid lead formulation, which has been selected for evaluation in a Phase 1 clinical trial (ClinicalTrials.gov Identifier NCT 02579226). This work clearly demonstrates the importance of assessing a wide range of drug release rates during formulation screening as a critical step for new drug product development, and how utilizing hydrophobic ion pairing enabled this promising nanoparticle formulation to proceed into clinical development.
authors.affiliation: BIND Therapeutics, 325 Vassar Street, Cambridge, MA 02139, USA.
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Song
authors.affiliation: BIND Therapeutics, 325 Vassar Street, Cambridge, MA 02139, USA.
authors.forename: Eyoung
authors.initials: E
authors.lastname: Shin
authors.affiliation: BIND Therapeutics, 325 Vassar Street, Cambridge, MA 02139, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: BIND Therapeutics, 325 Vassar Street, Cambridge, MA 02139, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Nolan
authors.affiliation: BIND Therapeutics, 325 Vassar Street, Cambridge, MA 02139, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Low
authors.affiliation: BIND Therapeutics, 325 Vassar Street, Cambridge, MA 02139, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Parsons
authors.affiliation: BIND Therapeutics, 325 Vassar Street, Cambridge, MA 02139, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Zale
authors.affiliation: Oncology iMED, AstraZeneca, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Ashton
authors.affiliation: Pharmaceutical Science, AstraZeneca, Macclesfield, Cheshire SK10 2NA, UK.
authors.forename: Marianne
authors.initials: M
authors.lastname: Ashford
authors.affiliation: BIND Therapeutics, 325 Vassar Street, Cambridge, MA 02139, USA.
authors.forename: Mir
authors.initials: M
authors.lastname: Ali
authors.affiliation: BIND Therapeutics, 325 Vassar Street, Cambridge, MA 02139, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Thrasher
authors.affiliation: BIND Therapeutics, 325 Vassar Street, Cambridge, MA 02139, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Boylan
authors.affiliation: BIND Therapeutics, 325 Vassar Street, Cambridge, MA 02139, USA. Electronic address: GregTroiano@bindtherapeutics.com.
authors.forename: Greg
authors.initials: G
authors.lastname: Troiano
mesh_terms: D000083:Acetanilides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D019826:Cholic Acid / Q000737:chemistry; D003840:Deoxycholic Acid / Q000737:chemistry; D004143:Dioctyl Sulfosuccinic Acid / Q000737:chemistry; D016503:Drug Delivery Systems; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D009284:Naphthols / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010755:Organophosphates / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D011799:Quinazolines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D011923:Rats, Nude; D017208:Rats, Wistar; D047368:Tumor Burden / Q000187:drug effects
chemical_list: C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; C000624274:AZD2811; D000083:Acetanilides; D000970:Antineoplastic Agents; D009284:Naphthols; D010755:Organophosphates; D011355:Prodrugs; D011799:Quinazolines; C542623:monomethoxypolyethyleneglycol-polylactide block copolymer; D003840:Deoxycholic Acid; D004143:Dioctyl Sulfosuccinic Acid; D011092:Polyethylene Glycols; C004368:pamoic acid; D019826:Cholic Acid; C050175:1-hydroxy-2-naphthoic acid
keywords: Adjustable release rate; Counterions; Drug release kinetics; In situ hydrophobic ion paring; Nanoparticles; PLA–PEG