Abstract
The delivery of peptide drugs to the brain is challenging, principally due to the blood brain barrier and the low metabolic stability of peptides. Exclusive delivery to the brain with no peripheral exposure has hitherto not been demonstrated with brain quantification data. Here we show that polymer nanoparticles encapsulating leucine5-enkephalin hydrochloride (LENK) are able to transport LENK exclusively to the brain via the intranasal route, with no peripheral exposure and nanoparticle localisation is observed within the brain parenchyma. Animals dosed with LENK nanoparticles (NM0127) showed a strong anti-nociceptive response in multiple assays of evoked and on going pain whereas animals dosed intranasally with LENK alone were unresponsive. Animals did not develop tolerance to the anti-hyperalgesic activity of NM0127 and NM0127 was active in morphine tolerant animals. A microparticulate formulation of clustered nanoparticles was prepared to satisfy regulatory requirements for nasal dosage forms and the polymer nanoparticles alone were found to be biocompatible, via the nasal route, on chronic dosing.
Highlights
The delivery of peptides to the brain is challenging, not merely because of the blood brain barrier and because peptides have a very short plasma half life and are frequently not detected in the plasma on intravenous administration [1]
DORs reside in the cerebral cortex, putamen, caudate nucleus, nucleus accumbens and hippocampus of humans [6] and exclusive brain delivery, via a non-parenteral route of administration, enables leucine5enkephalin hydrochloride (LENK) to be considered as a potential analgesic
Monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan, Mw = 18.6 ± 4.6 kDa, Mw/Mn = 1.033 ± 0.027, mole% palmitoylation = 15 ± 1.3, mole% quaternary ammonium groups = 8 ± 0.8) and LENK by vortexing for 5 min in water for injection BP, the pH adjusted to pH = 5.8 with NaOH (1 M) prior to probe sonicating (Qsonica, UK) with the instrument set at 30% of its maximum output for 10 min on ice
Summary
The delivery of peptides to the brain is challenging, not merely because of the blood brain barrier and because peptides have a very short plasma half life and are frequently not detected in the plasma on intravenous administration [1]. We show that the use of an intranasal nanoparticle delivery system enables the delivery of a metabolically unstable [3], δ selective opioid receptor (DOR) [4][5] agonist, leucine5enkephalin hydrochloride (LENK), directly and exclusively to the brain. DORs reside in the cerebral cortex, putamen, caudate nucleus, nucleus accumbens and hippocampus of humans [6] and exclusive brain delivery, via a non-parenteral route of administration, enables LENK to be considered as a potential analgesic. Chronic pain affects 19% of European adults, with nearly half being poorly managed by current therapies and with devastating consequences on their quality of life [7]. Breakthrough pain requires remedies with a rapid onset of action
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