The Pharmacokinetics of Drug Delivery to the Upper Nasal Space: A Review of INP105 Development

Shrewsbury, Stephen B.; Davies, Greg; McConnachie, Lisa A.; Hoekman, John

doi:10.18103/mra.v10i9.2971

Cited by 5 publications

(4 citation statements)

References 21 publications

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“…50 Therefore, devices that have been developed for humans might result in mechanical damage when used in monkeys. The POD device that was used in this study was also reported in the past for intranasal delivery in primates, in both cynomolgus monkeys, 51 as in the current study, and in Rhesus macaques. 52 In both cases, no damage was reported in the monkeys, but in both studies, histopathological evaluation was not performed, and the administration was performed once, and was not repeated administration, as in our study.…”

Section: Discussionmentioning

confidence: 74%

Preclinical In-Vivo Safety of a Novel Thyrotropin-Releasing Hormone-Loaded Biodegradable Nanoparticles After Intranasal Administration in Rats and Primates

et al. 2023

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Thyrotropin-releasing hormone (TRH) and TRH-like peptides carry a therapeutic potential for neurological conditions. Nanoparticles (NP) made of the biodegradable polymer, Poly(Sebacic Anhydride) (PSA), have been developed to carry TRH, intended for intranasal administration to patients. There is limited information on the safety of biodegradable polymers when given intranasally, and therefore, we have performed two preclinical safety and toxicity studies in cynomolgus monkeys and rats using TRH-PSA nanoparticles. The rats and monkeys were dosed intranasally for 42 days or 28 days, respectively, and several animals were followed for additional 14 days. Animals received either placebo, vehicle (PSA), or different concentrations of TRH-PSA. No systemic adverse effects were seen. Changes in T3 or T4 concentrations were observed in some TRH-PSA-treated animals, which did not have clinical or microscopic correlates. No effect was seen on TSH or prolactin concentrations. In the monkey study, microscopic changes in the nasal turbinates were observed, which were attributed to incidental mechanical trauma caused during administration. Taken together, the TRH-loaded PSA NPs have proven to be safe, with no local or systemic adverse effects attributed to the drug loaded nanoparticles. These findings provide additional support to the growing evidence of the safety of peptide-loaded NPs for intranasal delivery and pave the way for future clinical trials in humans.

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Section: Discussionmentioning

confidence: 74%

Preclinical In-Vivo Safety of a Novel Thyrotropin-Releasing Hormone-Loaded Biodegradable Nanoparticles After Intranasal Administration in Rats and Primates

et al. 2023

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“…A subsequent program, INP105, with a spray-dried powder formulation of olanzapine [ 66 ], showed in phase 1 a similar C max and AUC as the same dose administered by intramuscular injection but with a faster T max , but with no approved IV formulation of olanzapine to compare against, absolute bioavailability could not be determined in this study ( Figure 2 b). The POD powder programs (both INP105 and INP103/107 with levodopa/carbidopa) [ 67 ] benefited from the previous development of both rodent and primate versions of the POD which speeded formulation development and pharmacokinetic characterization before, or even during, human trials [ 68 ], with the structure and function of the non-human primate nose being most similar to that of humans [ 69 ].…”

Section: Systemic Deliverymentioning

confidence: 99%

The Upper Nasal Space: Option for Systemic Drug Delivery, Mucosal Vaccines and “Nose-to-Brain”

Shrewsbury

2023

Pharmaceutics

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Sino-nasal disease is appropriately treated with topical treatment, where the nasal mucosa acts as a barrier to systemic absorption. Non-invasive nasal delivery of drugs has produced some small molecule products with good bioavailability. With the recent COVID pandemic and the need for nasal mucosal immunity becoming more appreciated, more interest has become focused on the nasal cavity for vaccine delivery. In parallel, it has been recognized that drug delivery to different parts of the nose can have different results and for “nose-to-brain” delivery, deposition on the olfactory epithelium of the upper nasal space is desirable. Here the non-motile cilia and reduced mucociliary clearance lead to longer residence time that permits enhanced absorption, either into the systemic circulation or directly into the CNS. Many of the developments in nasal delivery have been to add bioadhesives and absorption/permeation enhancers, creating more complicated formulations and development pathways, but other projects have shown that the delivery device itself may allow more differential targeting of the upper nasal space without these additions and that could allow faster and more efficient programs to bring a wider range of drugs—and vaccines—to market.

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“…75 Different drug delivery device combinations are also being developed, as seen in the propellantpowered delivery device for INP105 that is designed to target drug delivery to the upper nasal cavity and has been tested in preclinical and clinical trials. 76,77 Compounds may cross the epithelial cell layer using paracellular (via tight junctions) or transcellular processes, then be transported via the general circulation to the brain, passing through the bloodbrain barrier. 64 Systemic transport results in rapid delivery to the brain, and evidence from animal models suggests that the systemic pathway predominates for the delivery of benzodiazepines to the brain, 78 though recent data have also implicated a direct-to-brain pathway.…”

Section: Intranasal Drug Delivery and Transport To The Brainmentioning

confidence: 99%

Alternative Approaches for Addressing Acute Agitation in Schizophrenia and Bipolar Disorder

Citrome,

Correll,

San

et al. 2024

Prim. Care Companion CNS Disord.

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Importance:The prompt effective treatment of acute agitation among patients with schizophrenia or bipolar disorder can alleviate distressing symptoms for the patient and decrease the risk of escalation to aggression and the potential for serious harm to the patient, health care providers, and others.Observations: A commonly used approach for the management of acute agitation has been the intramuscular administration of antipsychotic medications and/or benzodiazepines. However, US Food and Drug Administration-approved treatments with alternative routes of delivery now include inhaled loxapine powder and, more recently, dexmedetomidine sublingual film. Two formulations of intranasal olanzapine for acute agitation are in development. Conclusions and Relevance:Intranasal formulations offer the potential for favorable pharmacokinetics and onset of action combined with ease of delivery obviating the need for injections and are thus consistent with patient-centered factors such as preference and selfadministration. In this review, alternative methods of medication delivery are discussed, with an emphasis on the potential for intranasal administration to treat acute agitation in adult patients with schizophrenia or bipolar disorder.

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The Pharmacokinetics of Drug Delivery to the Upper Nasal Space: A Review of INP105 Development

Cited by 5 publications

References 21 publications

Preclinical In-Vivo Safety of a Novel Thyrotropin-Releasing Hormone-Loaded Biodegradable Nanoparticles After Intranasal Administration in Rats and Primates

Preclinical In-Vivo Safety of a Novel Thyrotropin-Releasing Hormone-Loaded Biodegradable Nanoparticles After Intranasal Administration in Rats and Primates

The Upper Nasal Space: Option for Systemic Drug Delivery, Mucosal Vaccines and “Nose-to-Brain”

Alternative Approaches for Addressing Acute Agitation in Schizophrenia and Bipolar Disorder

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