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Direct Drug Delivery of Low-Permeable Compounds to the Central Nervous System Via Intranasal Administration in Rats and Monkeys

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Abstract

Purpose

Intranasal administration enhances drug delivery to the brain by allowing targeted-drug delivery. Here, we investigated the properties that render a compound suitable for intranasal administration, and the differences between rodents and non-human primates in delivery to the brain.

Methods

The delivery of 10 low-permeable compounds to the brain, including substrates of efflux drug transporters expressed in the blood-brain barrier (didanosine, metformin, zolmitriptan, cimetidine, methotrexate, talinolol, ranitidine, atenolol, furosemide, and sulpiride) and two high-permeable compounds (ropinirole and midazolam) was evaluated following intranasal and intravenous administration in rats. Six of the 12 compounds (metformin, cimetidine, methotrexate, talinolol, sulpiride, and ropinirole) were also evaluated in monkeys, which have a similar nasal cavity anatomical structure to humans.

Results

In rats, most of the low-permeable compounds displayed an obvious increase in the brain/plasma concentration ratio (Kp) by intranasal administration (despite their substrate liability for efflux drug transporters); this was not observed with the high-permeable compounds. Similarly, intranasal administration increased Kp for all low-permeable compounds in monkeys.

Conclusions

Compound permeability is a key determinant of Kp increase by intranasal administration. This route of administration is more beneficial for low-permeable compounds and enhances their delivery to the brain in rodents and non-human primates.

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Abbreviations

AUC:

Area under the plasma concentration-time curve

BBB:

Blood-brain barrier

BCRP:

Breast cancer resistance protein

CNS:

Central nervous system

Kp :

Tissue/plasma concentration ratio

LC/MS/MS:

Liquid chromatography/tandem mass spectrometry

P-gp:

P-glycoprotein

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Acknowledgement and Disclosures

All authors were employees of Takeda Pharmaceutical Company Limited when the study was performed. The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Co., Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan

    Shinji Iwasaki, Syunsuke Yamamoto, Noriyasu Sano, Kimio Tohyama, Yohei Kosugi, Atsutoshi Furuta, Teruki Hamada, Tomoko Igari, Yasushi Fujioka, Hideki Hirabayashi & Nobuyuki Amano

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  1. Shinji Iwasaki
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Correspondence to Shinji Iwasaki.

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Supplemental Fig. 1

Time profiles of plasma concentration in rats after intravenous (open circle) or intranasal administration (closed square) (mean ± S.D., n = 3 / time point). (PNG 250 kb)

High resolution image

(EPS 93 kb)

Supplemental Fig. 2

Time profiles of olfactory bulb concentration in rats after intravenous (open circle) or intranasal administration (closed square) (mean ± S.D., n = 3 / time point). The concentration below the quantitation limit was assumed to be 0 and not shown in the figure. The bottom of the error bar, which extends to a negative y-axis value, is not shown. (PNG 254 kb)

High resolution image

(EPS 91 kb)

Supplemental Fig. 3

Time profiles of olfactory tract concentration in rats after intravenous (open circle) or intranasal administration (closed square) (mean ± S.D., n = 3 / time point). The concentration below the quantitation limit was assumed to be 0 and not shown in the figure. The bottom of the error bar, which extends to a negative y-axis value, is not shown. (PNG 248 kb)

High resolution image

(EPS 90 kb)

Supplemental Fig. 4

Time profiles of trigeminal nerve concentration in rats after intravenous (open circle) or intranasal administration (closed square) (mean ± S.D., n = 3 / time point). The bottom of the error bar, which extends to a negative y-axis value, is not shown. (PNG 255 kb)

High resolution image

(EPS 94 kb)

Supplemental Fig. 5

Time profiles of the rest of the brain concentration in rats after intravenous (open circle) or intranasal administration (closed square) (mean ± S.D., n = 3 / time point). The concentration below the quantitation limit was assumed to be 0 and not shown in the figure. The bottom of the error bar, which extends to a negative y-axis value, is not shown. (PNG 243 kb)

High resolution image

(EPS 90 kb)

Supplemental Fig. 6

The relationship of Kp,in/Kp,iv calculated by AUC and at 0.25 h in rat olfactory bulb (A), olfactory tract (B), trigeminal nerve (C), and rest of the brain (D). Solid line represents line of unity. The area between dashed lines represents an area within a 2-fold error. (PNG 96 kb)

High resolution image

(EPS 143 kb)

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Iwasaki, S., Yamamoto, S., Sano, N. et al. Direct Drug Delivery of Low-Permeable Compounds to the Central Nervous System Via Intranasal Administration in Rats and Monkeys. Pharm Res 36, 76 (2019). https://doi.org/10.1007/s11095-019-2613-8

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