Sustained Pulmonary Delivery of a Water-Soluble Antibiotic Without Encapsulating Carriers.
OBJECTIVE
Traditional polymeric nanoparticle formulations for prolonged local action during inhalation therapy are highly susceptible to muco-ciliary clearance. In addition, polymeric carriers are typically administered in high doses due to finite drug loading. For toxicological reasons, these carriers and their degradation byproducts are undesirable for inhalation therapy, particularly for chronic use, due to potential lung accumulation.


METHODS
We synthesized a novel, insoluble prodrug (MRPD) of a time-dependent β-lactam, meropenem, and formulated MRPD into mucus-penetrating crystals (MRPD-MPCs). After characterizing their mucus mobility (in vitro) and stability, we evaluated the lung pharmacokinetics of intratracheally-instilled MRPD-MPCs and a meropenem solution in guinea pigs.


RESULTS
Meropenem levels rapidly declined in the lungs of guinea pigs receiving meropenem solution compared to those given MRPD-MPCs. At 9 h after dosing, drug levels in the lungs of animals that received meropenem solution dropped to 12 ng/mL, whereas those that received MRPD-MPCs maintained an average drug level of ≥1,065 ng/mL over a 12-h period.


CONCLUSIONS
This work demonstrated that the combination of prodrug chemistry and mucus-penetrating platform created nanoparticles that produced sustained levels of meropenem in guinea pig lungs. This strategy represents a novel approach for sustained local drug delivery to the lung without using encapsulating matrices.
Kala Pharmaceuticals, Inc., 100 Beaver Street, Suite 201, Waltham, Massachusetts, 02453, USA. winston.ong@kalarx.com.
Winston
W
Ong
Kala Pharmaceuticals, Inc., 100 Beaver Street, Suite 201, Waltham, Massachusetts, 02453, USA.
Pawel
P
Nowak
Kala Pharmaceuticals, Inc., 100 Beaver Street, Suite 201, Waltham, Massachusetts, 02453, USA.
Yen
Y
Cu
Kala Pharmaceuticals, Inc., 100 Beaver Street, Suite 201, Waltham, Massachusetts, 02453, USA.
Lisa
L
Schopf
Kala Pharmaceuticals, Inc., 100 Beaver Street, Suite 201, Waltham, Massachusetts, 02453, USA.
James
J
Bourassa
Kala Pharmaceuticals, Inc., 100 Beaver Street, Suite 201, Waltham, Massachusetts, 02453, USA.
Elizabeth
E
Enlow
Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, 02114, USA.
Samuel M
SM
Moskowitz
Kala Pharmaceuticals, Inc., 100 Beaver Street, Suite 201, Waltham, Massachusetts, 02453, USA.
Hongming
H
Chen
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D006168:Guinea Pigs; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008297:Male; D000077731:Meropenem; D009093:Mucus / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry; D012995:Solubility; D012996:Solutions / Q000008:administration & dosage / Q000737:chemistry; D013845:Thienamycins / Q000008:administration & dosage / Q000737:chemistry; D014867:Water / Q000737:chemistry*
D000900:Anti-Bacterial Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D011355:Prodrugs; D012996:Solutions; D013845:Thienamycins; D014867:Water; D000077731:Meropenem
antibiotics; drug delivery; meropenem; mucus; nanoparticle; prodrug