Formulation and device design to increase nose to brain drug delivery

Accepted Manuscript Formulation and Device Design to Increase Nose to Brain Drug Delivery Zachary N. Warnken, Hugh D.C. Smyth, Alan B. Watts, Steve Weitman, John G. Kuhn, Robert O. Williams, III PII:

S1773-2247(16)30130-7

DOI:

10.1016/j.jddst.2016.05.003

Reference:

JDDST 200

To appear in:

Journal of Drug Delivery Science and Technology

Received Date: 4 April 2016 Revised Date:

11 May 2016

Accepted Date: 12 May 2016

Please cite this article as: Z.N. Warnken, H.D.C. Smyth, A.B. Watts, S. Weitman, J.G. Kuhn, R.O. Williams III., Formulation and Device Design to Increase Nose to Brain Drug Delivery, Journal of Drug Delivery Science and Technology (2016), doi: 10.1016/j.jddst.2016.05.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

2

Formulation and Device Design to Increase Nose to Brain Drug Delivery

3

Zachary N. Warnken (1), Hugh D.C. Smyth*(1), Alan B. Watts (1, 2), Steve Weitman (3),

4

John G. Kuhn (4) and Robert O. Williams III*(1)

5

(1) Division of Pharmaceutics, College of Pharmacy, University of Texas at Austin, Austin, TX

6

78712

7

(2) Drug Dynamics Institute, College of Pharmacy, University of Texas at Austin, Austin,

8

TX 78712

9

(3) Institute for Drug Development, Cancer Therapy and Research Center (CTRC),

10

University of Texas Health Science Center at San Antonio, 7979 Wurzbach Dr., San

11

Antonio, TX 78229, USA

12

(4) Division of Pharmacotherapy, College of Pharmacy, University of Texas at Austin,

13

Austin, TX 78712

EP

TE D

M AN U

SC

RI PT

TITLE:

14 15

*

AC C

1

Corresponding Authors: Hugh D.C. Smyth, College of Pharmacy (Mailstop A1920), University of Texas at Austin, Austin, TX 78712-1074, USA. Tel. +1 505 514 8737 Fax. +1 512 471 7474 Email Address: [email protected] (H.D.C. Smyth)

Robert O. Williams III, College of Pharmacy (Mailstop A1920), University of Texas at Austin, Austin, TX 78712-1074, USA. Tel.: +1 512 471 4681; fax: +1 512 471 7474. Email Address: [email protected] (R. O. Williams III)

1

ACCEPTED MANUSCRIPT

1

KEYWORDS nasal drug delivery; nose to brain; formulation; drug targeting; brain delivery;

3

nasal devices

RI PT

2

4

ABBREVIATIONS: CNS-Central Nervous System, BBB- Blood-brain barrier, CSF-

6

cerebrospinal fluid, Insulin Growth Factor-I (IGF-I), Area under the curve (AUC), Direct

7

Targeting Efficiency (DTE), intranasal (i.n.), intravenous (i.v.), poly(ethylene glycol)-poly

8

(lactic acid) (PEG-PLA), poly(lactic-co-glycolic acid) (PLGA), risperidone (RSP), risperidone

9

nanoemulsion (RNE), risperidone mucoadhesive nanoemulsion (RMNE), Solid lipid

M AN U

10

SC

5

Nanoparticle (SLN)

11

ABSTRACT A major limiting factor for the treatment of central nervous system (CNS) related

13

disorders is the inability for drug substances to cross the blood-brain barrier. Some medications

14

may possess dose-limiting systemic side effects that hinder their ability to reach maximum

15

effective concentrations in the CNS.

16

Over the last several decades, scientists have studied the ability for drugs to be transported from

17

the nose directly to the brain, and compared to intravenous injections, many studies have

18

reported higher brain concentrations from formulations administered intranasally. The primary

19

focus of this paper is to review the formulation and device approaches that have been reported to

20

increase drug delivery into the CNS through the nose-to-brain delivery pathway.

AC C

EP

TE D

12

21 22

TEXT

2

ACCEPTED MANUSCRIPT

1. Introduction

2

There are several barriers that a drug must overcome to treat a CNS related disorder and provide

3

a pharmacological response. These include the blood-brain barrier (BBB) and the blood-

4

cerebrospinal fluid barrier.1 The BBB is comprised of tight junctions, an enzymatic barrier, and

5

transport proteins that selectively prevent substances from entering the brain interstitial fluid

6

from the blood.2 Over the last several decades, it has been discovered that materials can be

7

transported directly to the brain interstitial fluid and cerebrospinal fluid when administered

8

intranasally.3,4 By using intranasal administration, it is possible to circumvent the barriers of the

9

BBB by taking advantage of the only place the CNS is in direct contact with the environment,

10

the olfactory epithelium.4 In bypassing the BBB, drugs that normally cannot enter the CNS may

11

be found to be therapeutically beneficial when administered intranasally. In addition, drugs that

12

pass the BBB but require large doses to provide therapeutically relevant brain levels, may be

13

effective at significantly lower doses, with a subsequent decrease adverse effects.5 In the past,

14

invasive methods such as intraparenchymal, intrathecal, and intracerebroventricular injections

15

have been used to achieve clinically relevant brain concentrations for therapeutic efficacy. More

16

recently, semi-invasive methods that transiently permeabilize the BBB have been reported6,7.

17

However, using targeted administration to the olfactory epithelium, it may be possible to achieve

18

the same effects in a patient-friendly manner that is conducive for chronic therapy.1 In animal

19

models, it has been shown that small molecules8, peptides4 and even viruses9 can reach the brain

20

using direct nose-to-brain pathways. Direct nose-to-brain delivery refers to intranasal

21

administration of a drug substance to the nasal cavity followed by absorption and transport of the

22

drug directly into the brain, bypassing the BBB. Limitations of nose-to-brain delivery have also

AC C

EP

TE D

M AN U

SC

RI PT

1

3

ACCEPTED MANUSCRIPT

been identified, and include a relatively small volume for administration of the drug, limited

2

surface area of the olfactory epithelium and short retention time for drug absorption.10

3

Despite these potential limitations, the nasal route of administration for brain delivery has shown

4

promise for therapeutic efficacy based on animal models and clinical trials in humans11,12 For an

5

in-depth review of the mechanisms and pathways by which drugs are transported to the brain

6

from the nose, readers are pointed to previous works by Dhuria et al.13, Pardeshi et al.8,

7

Lockhead et al.14 and Baker et al.15 The present review is focused specifically on how

8

formulation and device design differences enhance drug uptake into the brain.

M AN U

SC

RI PT

1

9

2. Nasal Formulations to Enhance Brain Drug Delivery

11

As with other routes of drug delivery, formulation design has been shown to help in overcoming

12

many of the barriers for direct nose-to-brain drug delivery. Table 1 provides a list of examples

13

that have so far been reported in the literature on formulations, and their effects on nose-to-brain

14

delivery. As can be seen in Table 1, formulations that have so far been utilized to enhance nose-

15

to-brain delivery include: solutions, microemulsion, mucoadhesive formulations, polymeric

16

nanoparticles, lipid-based nanoparticles as well as novel combination therapies. The formulation

17

of choice may be greatly influenced by the physicochemical properties of the drug.

18

Table 1. Drugs and Their Formulations Reported for Nose-to-Brain Delivery.

AC C

EP

TE D

10

Drug

Formulation Description

Animal Model

Disease State Being Treated

Results

Reference

5-FU

Solution

Rats pre-dosed with acetazolamide

CNS malignancy

104% increased brain uptake compared to i.v.

16

Bromocriptine

Chitosan Nanoparticles

Mice

Parkinson’s Disease

Showed significant increase in

17

4

ACCEPTED MANUSCRIPT

(~160 nm)

dopamine levels DTE-4.13 compared with 3.38 for i.n. plain solution

18

Carbamazepine Hypromellose/Carbopol Rats Gel

Epilepsy

Significantly higher brain uptake compared to i.v.

19

Carbamazepine Thermoreversible Gel

Epilepsy

DTE - 0.98

20

Chitosan/HP-β-CD solution

Rats

Mice

RI PT

Depression

Buspirone

i.n. and i.v. provide similar blood/plasma ratios

In Situ Gelling Microemulsion

Rats

Brain tumor/ Alzheimer’s Disease

DTE-6.5

21

Donepezil

Chitosan Nanoparticles (~150-200 nm)

Rats

Alzheimer’s Disease

Significantly higher brain concentrations from nanoparticles

22

Doxepin

Thermoreversible Gel

Mice

Depression

No difference in pharmacodynamic endpoint

23

Duloxetine

Lipid Nanocarrier (~80-130 nm)

Rats

Depression

DTE – 757.14% compared to 287.34% from solution

24

Estradiol

Cyclodextrin

GDF-5

Microemulsion

TE D

M AN U

SC

Curcumin

Alzheimer’s Disease

AUCCSF/AUCplasma 1.60 which was significantly higher than 0.61 from i.v.

25

Rats

Parkinson’s Disease

Significantly higher midbrain concentrations compared to acidic solution

26

EP

Rats

Mucoadhesive Solution

Rats pre-dosed with acetazolamide

CNS malignancy

195% increase in uptake compared to i.n. without acetazolamide; 75% reduction in brain tumor weight

5

Methotrexate

Solution

Rats

CNS malignancy

DTE- 21.7%

27

Morphine

Solution (PBS buffer at pH 7.4)

Rats

Pain

Brain/Plasma AUC ratio of 3 after i.n. use and 0.1 after i.v. use

28

Nimodipine

Microemulsion

Rats

Stroke, reduce

Higher AUC in olfactory bulb but

29

AC C

Methotrexate

5

ACCEPTED MANUSCRIPT

dementia

lower AUC in rest of brain after i.n. compared with i.v. treatment

Nanomicellar Carrier (~18-380 nm)

Rats

Schizophrenia/Bipolar DTE- 520.26% Disorder

30

Olanzapine

PLGA Nanoparticles (~ 90 nm)

Rats

Schizophrenia/Bipolar 10.86 times higher Disorder brain uptake compared to i.n. solution alone

31

Olanzapine

Mucoadhesive Nanoemulsion ( ~20 nm)

Rats

Schizophrenia/Bipolar DTE-890% Disorder compared to 550% from i.n. solution

32

Paliperidone

Mucoadhesive Microemulsion

Rats

Schizophrenia/Bipolar DTE-320.69%; 1.74-fold higher than nasal solution alone

Raltitrexed

Solution (PBS pH 8)

Rats

Rasagiline

Thermosensitive Gel

Remoxipride

M AN U

SC

RI PT

Olanzapine

33

DTE for Olfactory Bulb, Cerebrum and cerebellum was 127,120 and 71 respectively

34

Rabbits

Parkinson’s Disease

Significant improvement in brain uptake from gel formulations

35

Solution (Normal Saline)

Rats

Psychosis

~50% increase in brain/plasma AUC

36

Risperidone

Mucoadhesive Nanoemulsion (~ 16 nm)

Rats

Schizophrenia/Bipolar DTE-476% Disorder

37

Risperidone

Solid Lipid Nanoparticles (~150 nm)

Mice

Schizophrenia/Bipolar 10-fold higher brain Disorder AUC compared to i.v. solution

38

Ropinirole

Temperature sensitive in situ gel with Chitosan and HPMC

Rats

Parkinson’s Disease

DTE-10.4 compared to 5.3 for solution alone

39

Saquinavir

Nanoemulsion (~180 nm)

Rats

CNS involved HIV infection

~62 times higher drug accumulation compared to i.v. suspension

40

Tacrine

Solution of Propylene glycol and Normal Saline

Mice

Alzheimer’s Disease

DTE-207.23%

41

Tacrine

Mucoadhesive Microemulsion

Mice

Alzheimer’s Disease

DTE-295.87%

42

Testosterone

Noseafix®

Mice

CNS Hormone

Significantly higher brain levels except

43

AC C

EP

TE D

CNS malignancy

6

ACCEPTED MANUSCRIPT

Mucoadhesive system

frontal cortex

Solution (Normal Saline)

Rats

Depression

No difference in CSF concentrations between i.n. or i.v.

44

Zidovudineprodrug

Solid Lipid Microparticles (16 and 7 µm)

Rats

CNS involved HIV infection

6-fold higher CSF uptake

45

Zolmitriptan

Micellar Nanocarrier (~23 nm)

Rats

Migraine

Significant increase in brain concentrations as soon as 30 min.; up to 120 min.

46

RI PT

UH-301

SC

1 2

Replacement

i.v.- intravenous, i.n.- intranasal, DTE- Direct Transport Efficiency, GDF-5- Growth Differentiation Factor-5, HIV- Human Immunodeficiency Virus

3 2.1 Solution Based Formulations

5

When formulating drugs as a solution (i.e., molecular dispersion), the physicochemical

6

properties of the drug will be the driving factor enhancing absorption. Studies on direct nose-to-

7

brain delivery with solutions have been done on a number of drugs (Table 1); including elements

8

like manganese47,48 and cobalt,49 to more complex small molecules like remoxipride36 and UH-

9

30144, and even proteins11,50–52. Thus, the physicochemical properties of the drug is an important

10

consideration when designing direct nose-to-brain dosage forms. Passive diffusion has been

11

shown to play a significant role in the delivery of small lipophilic molecules as reported by

12

Kandimalla et al. from diffusion cell permeability studies with hydroxyzine.53 To exemplify the

13

importance of size on this drug delivery, Pardeshi et al.8 compared the delivery of dopamine54, a

14

small molecule, to that of nerve growth factor, a relatively small secreted protein (MW=26,500

15

Da), and observed that brain concentrations were fivefold higher for dopamine than the protein

16

when dosed at the same concentration. Even though small lipophilic drugs are found to have the

17

highest brain levels after intranasal administration, hydrophilic drugs often show the largest

18

improvement in brain levels compared to other routes of administration.

AC C

EP

TE D

M AN U

4

Raltitrexed, a

7

ACCEPTED MANUSCRIPT

hydrophilic small molecule with a logP of -0.98, was studied to assess brain levels after

2

intranasal and intravenous administration. It was found that, depending on the section of brain, a

3

54-121 fold increase in the AUC was noted after intranasal administration when compared to

4

intravenous use in rats.34 Wang et al. performed similar experiments with methotrexate, another

5

hydrophilic drug with logP -1.98, and found that it provided greater than 13 fold higher CSF

6

AUC after nasal administration compared to intravenous administration.27 When comparing the

7

CSF concentrations from the Wang et al. study to those that use a brain tumor model5, it can be

8

inferred that the increase in CSF concentration may be sufficient for pharmacological activity.

9

Recently, brain distribution and efficacy studies have been reported with pralidoxime and

10

obidoxime solutions55. Krishnan et al55. report brain distribution of the compounds in rats was

11

consistent with direct nose-to-brain delivery. Pralidoxime and obidoxime are oximes which can

12

be used for treating organophosphate poisoning. However, their efficacy is limited by their

13

inability to effectively cross the BBB. Krishnan et al. also measured acetylcholinesterase return

14

from inhibition, the target for organophosphate poisoning, after intranasal administration of the

15

medication and found that nearly 90% of enzyme activity was brought back in the olfactory

16

region and anywhere from 4-13% recovered in other regions of the brain. Interestingly, it was

17

found that a solution formulation of the oximes was preferred over the attempted chitosan based

18

nanoemulsion or chitosan based nanoparticles due to loading efficiency and viscosity issues.

19

This serves as an excellent example that formulations must be tailored for efficiency and

20

compatibility with their eventual mode of delivery.

21

Solution formulations of macromolecules8,56 have presented evidence of direct transport in

22

animal studies including solutions of plasmids57, IGF-I51 and Nerve Growth Factor4. Research

AC C

EP

TE D

M AN U

SC

RI PT

1

8

ACCEPTED MANUSCRIPT

1

with arginine vasopressin58, insulin12, oxytocin11 and melanocortin melanocyte-stimulating

2

hormone/adrenocorticotropin4-1059

3

route.

4

The wide variety of substances that can be transported directly to the brain is promising for the

5

enablement and enhancement of treatment options for CNS-related disorders. While only a

6

limited number of the current studies in humans provide pharmacokinetic evidence for direct

7

nose-to-brain drug delivery, many experiments have compared pharmacodynamic endpoints after

8

intranasal

9

pharmacodynamic-pharmacokinetic studies in animals may provide more accurate predictive

10

models for assessing drugs undergoing direct nose-to-brain transport in humans than previously

11

used pharmacokinetic animal models. Predictive models are needed because direct

12

pharmacokinetic studies using brain concentrations of a drug in humans cannot be readily

13

obtained. An example of using a pharmacodynamic measurement for assessing drug delivery in

14

humans is the study by Pietrowsky et al.58. They reported the event-related potentials, which are

15

a measure of the brain’s electrical response to a stimulus, after administration with either

16

intranasal or intravenous arginine vasopressin. Aqueous based solution formulations are shown

17

to be effective drug delivery systems for water soluble small molecules and many peptides and

18

proteins and among other formulations, have been studied the most for direct brain delivery in

19

humans.

20

2.2 Mucoadhesive/Viscosity Increasing Agents

21

Different formulation techniques have been reported to overcome some of the barriers to nasal

22

drug delivery in hopes of increasing the amount delivered to the brain. A significant barrier is the

intravenous

administration.

Ruigrok

and

Lange60

explained

that

AC C

EP

TE D

M AN U

and

SC

RI PT

in humans supports the delivery of macromolecules via this

9

ACCEPTED MANUSCRIPT

mucociliary clearance present in the nasal cavity. Mucoadhesive and viscosity increasing agents

2

have been used in an attempt to increase drug residence time in the nasal cavity to allow for

3

better absorption.61 By increasing the viscosity of the formulation, with polymers such as

4

hypromellose or polyvinyl alcohol, it is possible to decrease mucociliary clearance.62,63 Even

5

though the cilia in the olfactory epithelium are non-motile, mucus clearance is still evident and

6

most likely caused by gravity and continuous mucus production by the Bowman’s gland.

7

Charlton et al.64 studied how some mucoadhesive agents can affect deposition and clearance to

8

the olfactory region in humans. Their experiments compared the clearance of different low-

9

molecular weight pectin and chitosan formulations in 12 human subjects administered as either

10

liquid drops or in the atomized from a nasal spray device. The formulations contained

11

fluorescein so that the deposition could be visually examined by endoscopy. Charlton et al. found

12

no statistical differences in the clearance from the olfactory region between the several polymer

13

formulations given as liquid drops. However, compared to the buffer solution control without

14

polymer and even a polymer formulation given as a nasal spray, the residence time and

15

deposition were significantly reduced. Mucoadhesive agents, such as pectin and chitosan studied

16

by Charlton et al. are effective at extending residence times at the olfactory epithelium, but other

17

factors such as delivery device are important for translating therapy to humans. It has been

18

shown that mucoadhesive and viscosity increasing agents are effective at increasing

19

bioavailability from nasal formulations designed for systemic delivery.65, To determine how the

20

addition of a mucoadhesive agent can influence the absorption of drugs into the brain, Khan et

21

al.18 compared brain concentrations of buspirone after intravenous administration, intranasally as

22

a solution without chitosan or cyclodextrins and intranasally as a solution with 1% chitosan and

23

5% hydroxypropyl-β-cyclodextrin. They found that the AUC in the brain was 2.5-times higher

AC C

EP

TE D

M AN U

SC

RI PT

1

10

ACCEPTED MANUSCRIPT

for buspirone in the mucoadhesive formulation than in the intravenous solution, and two-times as

2

high as buspirone solution when delivered intranasally. The cyclodextrins may have also

3

contributed to the increase in brain concentration by increasing the permeability of the drug

4

through the tight junctions of the nasal epithelium.18 Utilizing a novel formulation to increase

5

nasal residence time and improve brain delivery, Bank et al.43 compared brain concentrations

6

after nasal delivery of testosterone in Noseafix® gel, comprised of castor oil, oleoyl

7

polyoxyglycerides and amorphous silicon dioxide, to those measured after intravenous

8

administration. They found significantly higher brain levels in all parts of the brain except the

9

frontal cortex following intranasal administration. However, since the authors did not compare

10

intranasal administration of testosterone without Noseafix®, no conclusion was stated about the

11

effect the formulation had on increasing brain delivery. The increase in brain concentration may

12

be attributed to intranasal administration alone.

13

Barakat et al.19 studied nose-to-brain delivery of carbamazepine with the use of hypromellose

14

and Carbopol 974P to form a gel, in an attempt to reduce clearance and enhance CNS

15

bioavailability. They found the brain AUC-to-plasma AUC ratio was 4.31-times higher than

16

from intravenous therapy. Carbamazepine has also been formulated in an in situ gelling

17

formulation for direct nose-to-brain delivery.20 The formulation consisted of carbamazepine,

18

18% Pluronic F-127 and 0.2% Carbopol 974P, which is a thermoreversible gel. A

19

thermoreversible gel is liquid at room temperature, but quickly turns into a gel at body

20

temperature. This provides an extended residence in the nasal cavity. When compared to

21

intravenous administration of carbamazepine solution, Barakat et al. reported that the intranasal

22

formulation provided 100% systemic bioavailability. Even at early time points, they were unable

23

to detect significantly higher brain levels in the intranasal group. Intranasal administration was

AC C

EP

TE D

M AN U

SC

RI PT

1

11

ACCEPTED MANUSCRIPT

performed on rats that were lying either on their side or in the supine position. Body position

2

during intranasal administration plays a significant role on the deposition of the formulation in

3

the nasal cavity, possibly targeting the respiratory region instead of the olfactory66. Other studies

4

have reported on the effects that thermoreversible gels can have on direct nose-to-brain drug

5

delivery. Ravi et al.35 used poloxamer 407 and poloxamer 188 (1:1) with chitosan and Carbopol

6

to develop a thermoreversible gel with rasagiline mesylate. Compared to a nasal solution of

7

rasagiline in normal saline, the gel formulations exhibited significantly higher brain uptake. The

8

studies discussed report increased brain concentrations with the addition of agents which appear

9

to increase the residence time of the drug at the site of absorption. Although these agents have

10

been shown to be effective in increasing brain concentrations, it is difficult to discern if the

11

enhancement is alone due to the increases in residence time of the formulation, or if the

12

excipients alter the permeability of the nasal tissue, leading to increases in absorption. Although

13

the mechanisms of enhanced brain concentrations from these excipients remains unclear, their

14

applicability for developing an effective formulation remains unchanged.

15

In a different formulation that also exhibited gelling at body temperatures, Khan et al.39 formed

16

an in situ gel formulation comprised of chitosan and hypromellose to deliver ropinirole, and

17

found that the AUC in the brain was 8.5-times higher compared to intravenous administration

18

and nearly four times greater than the intranasally administered ropinirole solution.

19

has been formed into a thermoreversible gel formulated with chitosan and glycerophosphate.

20

Instead of accessing brain concentrations from homogenate brain tissue, the investigators

21

assessed efficacy by a forced swim test, yet they saw no significant difference in the duration of

22

immobility when tested23. In situ gel preparations which activate in the presence of ions have

23

also been developed and shown to form a gel in the presence of nasal secretions.67 These

AC C

EP

TE D

M AN U

SC

RI PT

1

Doxepin

12

ACCEPTED MANUSCRIPT

studies, also shown in Table 1, describe that formulating with excipients intended to increase the

2

drug’s residence time may allow an increase in the time the formulation is in contact with the

3

olfactory epithelium, which generally lead to an increase in the amount of drug delivered to the

4

brain. In many cases, for instance those incorporating chitosan18,39,68,it is difficult to discern if

5

the increases in brain concentrations are solely dependent on the increased residence time of the

6

formulations or from increased permeability across the olfactory epithelium.

SC

RI PT

1

7 2.3 Polymeric Nanoparticles

9

A favorable formulation method for many routes of administration is the formation of

10

nanosuspensions of drugs encapsulated in polymeric carriers. These carriers may provide

11

favorable characteristics to the drug like enhanced absorption, mucoadhesion and increased

12

stability. Bhavna et al.22 developed a nanosuspension formulation of donepezil, a cholinesterase

13

inhibitor, for enhancing brain targeting to treat Alzheimer’s disease. The nanosuspension is

14

formed by crosslinking chitosan with tripolyphosphate to form nanoparticles that encapsulate

15

donepezil. When tested in rats against donepezil suspension, the authors reported significantly

16

higher AUC and maximum concentration in the brain after administration with the

17

nanosuspension. The authors also observed significantly higher bioavailability with the

18

nanosuspension so whether or not the increase in brain concentrations was due to direct nose-to-

19

brain mechanisms is difficult to conclude.

20

nanoparticles loaded with bromocriptine.17 In this study they compared bromocriptine-loaded

21

nanoparticles given intranasally, bromocriptine-loaded nanoparticles given intravenously, and

22

bromocriptine solution given intranasally. They found that bromocriptine-loaded nanoparticles

23

given intranasally produced brain AUCs that were over two-fold greater than intravenous

AC C

EP

TE D

M AN U

8

In another paper, the authors tested chitosan

13

ACCEPTED MANUSCRIPT

administration of the nanoparticles. Both nanoparticle formulations showed higher brain and

2

plasma AUC values. A novel polymeric carrier developed by Gao et al.69 is comprised of wheat

3

germ agglutinin conjugated to poly (ethylene glycol)-poly (lactic acid) (PEG-PLA) in an effort to

4

increase absorption of nanoparticles to the brain. They used the nanoparticle carrier to

5

encapsulate coumarin and found a two-fold increase in brain concentrations after intranasal

6

administrations when compared to intranasal administration of unmodified PEG-PLA

7

nanoparticles. In a later study, Gao et al. determined if the nanoparticle carrier would be

8

applicable to transport peptides to the brain.70 They incorporated vasoactive intestinal peptide

9

into the wheat germ agglutinin conjugated PEG-PLA nanoparticles. When given intranasally,

10

the authors reported 5.6-7.7 fold higher brain levels from the conjugated nanoparticles when

11

compared to vasoactive intestinal peptide given intranasally as a solution. Additionally, they also

12

found higher brain levels from the conjugated nanoparticles compared to the peptide delivered in

13

unmodified nanoparticles. The results from this study are displayed in Figure 1, which shows the

14

concentrations of vasoactive intestinal peptide measured in the olfactory bulb and olfactory tract

15

(Figure 1A), cerebrum (Figure 1B) and cerebellum (Figure 1C) after administration with the

16

wheat germ agglutinin conjugated PEG-PLA nanoparticles, unmodified nanoparticles, or as a

17

solution. Higher concentrations in the olfactory region (Figure 1A) and the cerebellum (Figure

18

1C) provide some evidence that the pathway for transport of the nanoparticles into the brain is

19

along both the olfactory and trigeminal nerves. The novel carrier was assessed for toxicity issues

20

during intranasal use by analyzing concentrations of surrogate markers, such as tumor necrosis

21

factor alpha and wheat germ agglutinin specific antibodies, and concluded that the nanoparticles

22

were a safe agent for use in intranasal therapy targeting the brain.71 Seju et al.31 used one of the

23

most commonly used biodegradable polymers for nanoparticles, poly(lactic-co-glycolic acid)

AC C

EP

TE D

M AN U

SC

RI PT

1

14

ACCEPTED MANUSCRIPT

(PLGA).31,72 The authors loaded olanzapine, an atypical antipsychotic, into the PLGA

2

nanoparticles for intranasal delivery. The authors performed ex vivo permeation studies along

3

with pharmacokinetic studies in rats and found the nanoparticles were slower to diffuse across

4

the sheep nasal mucosa in the ex vivo study. However, in the pharmacokinetic study, they found

5

10.86 times higher drug accumulation in the brain after nanoparticle administration than the

6

olanzapine solution given intranasally, and 6.35 times higher than after drug solution given

7

intravenously. Studies with polymeric nanoparticles are not yet conclusive on whether or not the

8

particles are being translocated across the membrane. However, studies by Mistry et al.73

9

compared transport of 20 nm, 100 nm and 200 nm polystyrene particles with and without surface

10

modifications and concluded that irrespective of the size or surface modification studied,

11

particles were not transported across the epithelium. Gao et al.69 discussed that the enhanced

12

brain concentrations from the wheat germ agglutinin conjugated nanoparticles allowed binding

13

with the nasal mucosal surface and then the release of the drug. Bhavna et al. predicted that

14

enhancements in brain delivery are also due to the mucoadhesive nature of chitosan. However,

15

Fazil et al.74 performed confocal laser scanning microscopy with rhodamine loaded chitosan

16

nanoparticles and reported that intact particles were found in the brain. Seju et al.31 predicted that

17

olanzapine PLGA nanoparticles were transported as intact particles by endocytotic processes.

18

Future studies are required to determine if the transport of the individual nanoparticle takes place

19

for all nanoparticles, or if this is an advantage of a select few nanoparticle types. These studies,

20

summarized in Table 1, show the promise that polymeric nanoparticle carriers can have on the

21

delivery of both small molecules and peptides into the brain.

AC C

EP

TE D

M AN U

SC

RI PT

1

15

5

EP

2 3 4

Figure 1. Amount vs. time profiles for vasoactive intestinal peptide after intranasal administration in the olfactory bulb and olfactory tract (A), cerebrum (B) and cerebellum (C). (Reprinted with permission from Gao et al., 2007)

AC C

1

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

6

2.4 Co-administration Methods for Improved Delivery

7

The olfactory region receives its blood supply from the small branches off the ophthalmic artery,

8

while the respiratory region receives its blood supply from a large arterial branch from the

9

maxillary artery. As a result, the respiratory region is highly innervated with blood vessels, 16

ACCEPTED MANUSCRIPT

making it an ideal target for systemic drug absorption.13. Often researchers target the olfactory

2

region for nose-to-brain delivery, since this has fewer blood vessels contributing to plasma

3

concentrations, while providing access to the olfactory nerve pathways. Dhuria et al.75 studied

4

the effect phenylephrine, a vasoconstrictor used for nasal decongestion, would have on

5

increasing the brain to plasma AUC ratio. They tested brain concentrations after nasal

6

administration of one of two neuropeptides, hypocretin-1 or dipeptide L-Tyr-D Arg. The use of

7

the vasoconstrictor significantly decreased the amount of drug absorbed into the systemic

8

circulation (Figure 1); it also significantly increased the amount delivered to the olfactory bulb.

9

However, this resulted in decreases in the amount in the trigeminal nerve and about a 50%

10

decrease in the whole brain concentrations of the neuropeptides. Within the nasal cavity, the

11

amount of hypocretin-1 was higher in the olfactory epithelium than in the respiratory epithelium

12

when pretreated with the vasoconstrictor, however this was not the case for dipeptide L-Tyr-D

13

Arg which was found to have high levels in each tissue. Use of a vasoconstrictor to modify drug

14

absorption may be applicable for delivering some therapeutics to the brain depending on the risks

15

of systemic exposure and location of the target for therapy. Although it is not completely clear

16

how phenylephrine modified the amount of peptide found in the trigeminal nerve, Dhuria et al.

17

findings provide insight into the importance of the trigeminal nerves on the amount of

18

neuropeptides delivered to the back of the brain. The authors speculate that the decreased

19

trigeminal nerve concentration may be partially explained by the decreased concentration of

20

peptide in the respiratory epithelium. Recently, Lockhead et al76. have presented evidence that

21

intranasally absorbed macromolecules utilize perivascular spaces of cerebral blood vessels to

22

rapidly distribute throughout the brain. The differences in brain concentration in certain regions

23

of the brain, with and without vasoconstrictor treatment may be influenced by distribution

AC C

EP

TE D

M AN U

SC

RI PT

1

17

ACCEPTED MANUSCRIPT

mechanisms within the brain. However, future studies are required to better understand the

2

implications these bulk flow mechanisms have on the targeting of therapeutics intranasally. Little

3

evidence exists to definitively quantify the separate contributions diffusion, perivascular space

4

transportation and the trigeminal nerve pathway have on the amount of molecules reaching the

5

back of the brain.

6

improving CNS delivery, the CSF originates at the choroid plexus and eventually flows across

7

the cribriform plate and into the nasal lymphatics. Shingaki et al. tested the use of

8

acetazolamide5,16 , a carbonic anhydrase inhibitor which functions to decrease the production of

9

CSF, on rats. When rats were dosed with 5-FU with and without pre-administration of

10

acetazolamide, Shingaki et al. found significantly higher CSF levels with the concomitant use of

11

acetazolamide.16 Similar studies with methotrexate produced similar results.5 Co-administration

12

with acetazolamide leads to a decrease in CSF secretion, which provides an increase in direct

13

transport of drugs into the CSF. The use of matrix metalloproteinase-9, an endopeptidase which

14

plays a role in extracellular matrix degradation,

15

compounds into the brain52,76. Appu et al.52 pretreated rats with matrix metalloproteinase-9

16

before administration of chloramphenicol acetyltransferase, an active enzyme. At their 15 minute

17

time point there were significant increases in enzyme activity in the brainstem, midbrain and

18

cortex regions. As seen in the studies discussed, co-administration techniques can assist drug

19

delivery in various ways, including targeting of drug uptake, decreasing clearance of the

20

medication from the brain and increasing uptake of the drug into the brain.

RI PT

1

has been reported to increase uptake of

AC C

EP

TE D

M AN U

SC

Additional brain physiology mechanisms have also been exploited for

21 22

2.5 Permeability Enhancing

18

ACCEPTED MANUSCRIPT

The nasal epithelium can be a rate-limiting barrier for transport of drugs directly to the brain. In

2

targeting drug delivery to the system circulation, many agents have been used to increase the

3

permeation of drugs across the epithelium.77–82 Agents used to increase the permeability across a

4

membrane are referred to as permeation enhancers. Permeation enhancers have also been used to

5

overcome this barrier for targeting delivery to the CNS. Since the nasal epithelial layer is

6

comprised of tight junctions, permeation enhancers which open tight junctions may be useful in

7

improving drug delivery to the brain. Some studies have used borneol83, chitosan and

8

cyclodextrins18,25 to help improve direct nose-to-brain drug transport (Table 1).

9

2.6 Lipid Based Drug Delivery Systems

M AN U

SC

RI PT

1

Other methods to increase delivery of drugs to the brain use lipid components like

11

microemulsions. Microemulsions can increase the concentration of hydrophobic drugs to be

12

delivered, as well as increase the permeability across membranes.84 Jogani et al.42 developed a

13

microemulsion formulation of tacrine for delivery to the brain. Firstly, they prepared a solution

14

of tacrine in propylene glycol and water and compared its brain delivery after intranasal and

15

intravenous administration. They found that the direct transport efficiency (DTE) was 207.23.41

16

DTE is a comparison of ratios of the AUC in the brain compared to plasma after intranasal

17

administration compared to intravenous administration, and is described by the following

18

equation:

AC C

EP

TE D

10

%DTE =

    /  i. n.  × 100%    =   i. v. 

19

Values greater than one, indicate that a higher brain/plasma ratio is obtained from intranasal

20

administrations as compared to intravenous administration. Jogani et al. then incorporated tacrine

19

ACCEPTED MANUSCRIPT

into a microemulsion formulation and a mucoadhesive microemulsion using the mucoadhesive

2

agent Carbopol 934P. The authors then compared brain delivery to mice from tacrine solution

3

given intranasally and intravenously to tacrine microemulsion and tacrine mucoadhesive

4

microemulsion given intranasally. The tacrine mucoadhesive microemulsion showed the highest

5

DTE of 295.87%, followed by the tacrine microemulsion (DTE 242.82%) and then tacrine

6

solution (DTE 207.23%). Many different investigators have looked at the effects microemulsion

7

and nanoemulsions with and without the use of mucoadhesive agents can have on direct nose-to-

8

brain delivery (Table 1).26,29,30,32,40,85,86For instance, Patel et al.33 studied the pharmacokinetics

9

from a paliperidone microemulsion formulation intended for delivery to the brain. Instead of

10

Carbopol 934P, Patel et al. used polycarbophil as a mucoadhesive agent in the formulation.

11

When given in rats, the mucoadhesive microemulsion formulation gave the highest DTE, 320.69

12

%, which was 1.74-fold higher than paliperidone given intranasally as a solution. Additionally,

13

the intranasal mucoadhesive microemulsion produced brain AUCs that were 2.43 times higher

14

than after intravenous administration of the microemulsion. One study used an in situ gelling

15

agent to increase the residence time in the nasal cavity after the microemulsion is administered.

16

Wang et al.21 developed a microemulsion using deacytylated gellan gum for ion activated in situ

17

gelling. When testing with curcumin, they found the DTE to be 6.50 and a brain AUC three

18

times that after curcumin injection. Curcumin has also been used to study the effects of an

19

optimized mucoadhesive nanoemulsion ex vivo permeation through sheep nasal mucosal as well

20

as in vitro toxicity studies. The mucoadhesive agent used with the nanoemulsion was chitosan.

21

The investigators found that their nanoemulsion did not cause noticeable toxicity issues and

22

increased curcumin permeation across the nasal mucosal.87 Risperidone has also been formulated

23

into a mucoadhesive nanoemulsion.37 The mucoadhesive agent added to the nanoemulsion was

AC C

EP

TE D

M AN U

SC

RI PT

1

20

ACCEPTED MANUSCRIPT

0.5% chitosan. The DTE was found to be 476 when tested in rats. The intravenous control in the

2

experiment was risperidone nanoemulsion, which shows higher brain intake was not due to the

3

nanoemulsion alone, but also contributed to by direct nose-to-brain pathways (Figure 2). The

4

locomotor activity was significantly reduced in mice when treated with any of the tested

5

formulations of risperidone. There was a significant reduction in activity from the risperidone

6

nanoemulsion and mucoadhesive nanoemulsion given intranasally compared to the risperidone

7

nanoemulsion given intravenously.

12

Figure 2. Brain risperidone concentration vs. time following administration with risperidone solution (i.n.), risperidone nanoemulsion (i.n.), mucoadhesive risperidone (i.n.) and risperidone nanoemulsion (i.v.). (Reprinted with permission from Kumar et al., 2008)

EP

9 10 11

AC C

8

TE D

M AN U

SC

RI PT

1

13

Risperidone has also been formulated as solid lipid nanoparticles for nose-to-brain delivery.38

14

Solid lipid nanoparticles reportedly provide many advantages over solution and drug suspension

15

dosage forms. They can entrap the drug, giving the ability to control release and potential to

16

improve stability. Additionally, they possess many of the advantages of microemulsion and

17

nanoemulsions. Solid lipid nanoparticles have recently received a lot of attention in delivery

21

ACCEPTED MANUSCRIPT

therapeutics using direct nose-to-brain drug delivery, as seen in table 1.38,45,88,89 Patel et al.38

2

entrapped risperidone into solid lipid nanoparticles (SLNs) and gave them intranasally and

3

intravenously. Risperidone solution was also given intravenously. It was shown that the SLNs

4

given intranasally produced a brain to plasma AUC ratio fivefold higher than the SLN

5

formulation given intravenously and tenfold higher than the risperidone solution given

6

intravenously. The brain AUC values after risperidone SLNs were administered intranasally and

7

intravenously were similar; however, the plasma AUC after intranasal administration was lower.

8

In theory, this would allow for equal efficacy while reducing systemic side effects by lowering

9

the plasma concentration. Similarly, Alam et al.24 studied the effects that a lipid nanocarrier of

10

duloxetine would have on brain delivery. They found the lipid nanocarrier formulations provided

11

about eight times higher brain concentrations when compared to intravenous administration of

12

duloxetine solution and a DTE of 757.14%. Intranasal administration of duloxetine solution

13

produced a DTE of 287.34%, showing that the lipid nanocarrier formulation was able to

14

significantly influence the amount delivered to the brain. Jain et al.46 produced a micellar

15

formulation of zolmitriptan, a medication currently indicated for migraine treatment. They found

16

that after administering the micellar formulation, there was about fivefold higher brain

17

concentrations in rats as soon as 30 minutes after administration, and the formulation continued

18

to show significantly higher brain concentrations up to 120 minutes. Further clinical study is

19

required to see how this could affect treatment of migraine, however it has been observed that it

20

is possible to increase zolmitriptan brain uptake in this manner.

21

3. Delivery Devices for Enhanced Nose to Brain Drug Delivery

22

Successful targeting of nose-to-brain drug delivery requires formulation to be administered in

23

such a way that the amount deposited on the olfactory epithelium is maximized. As can be seen

AC C

EP

TE D

M AN U

SC

RI PT

1

22

ACCEPTED MANUSCRIPT

in Table 1, there have been several studies focused on formulations to increase transport of

2

medications into the brain, however, the number of studies focused on the delivery devices to

3

target these medications for nose to brain delivery is more scarce. The deposition from various

4

nasal devices is typically reported as the amount or percent deposited in defined segments of the

5

nasal cavity. For a detailed discussion of the nasal cavity anatomy the reader is referred to

6

Clerico et al.90, Mygind et al.91 and Thomas et al.92

7

Currently, many of the market nasal preparations are delivered with meter-dosed pump sprays.

8

These pump sprays typically deliver between 25 and 200 µL per spray. This type of delivery

9

system is relatively easy for patients to use and reproducibly delivers accurate doses.93

10

Deposition from conventional pump sprays is typically isolated to the anterior regions of the

11

nasal cavity, encompassing the vestibule and nasal valve area85,94–96. In addition to alterations in

12

the nasal spray device, deposition can be influenced by formulation parameters such as viscosity,

13

resulting droplet size and resulting plume geometry among others. Spray products which product

14

a smaller plume angle have a larger percentage of the dose delivered to the turbinate region of

15

the nasal cavity95,96. Of the relatively small volume that is administrable utilizing meter-dosed

16

spray pumps, only around 2.5% is deposited in the area which corresponds to the olfactory

17

region97.

18

One of the oldest nasal delivery systems is nasal drops93. When administered correctly, nasal

19

drops spread over a larger area than nasal sprays, however, are often cleared faster than nasal

20

sprays as well94. As discussed previously, Charlton et al. reported that nasal drops possess higher

21

deposition in the olfactory region compared to nasal sprays, and when formulated with

22

mucoadhesive agents, are able to reduce the time in which the formulation is cleared from the

23

area. The longest mean residence time in the olfactory region achieved in the study was about 14

AC C

EP

TE D

M AN U

SC

RI PT

1

23

ACCEPTED MANUSCRIPT

minutes, compared to 1.3 minutes for control solution without any mucoadhesive agents64. An

2

important limitation of nasal drops, and nasal sprays for that matter, is that their efficacy can be

3

affected by patient administration technique. Nasal drops require complex maneuvers by patients

4

to achieve correct head positioning for proper administration 93.

5

In order to overcome the disadvantages associated with conventional nasal delivery systems with

6

regards to targeting the olfactory region, novel delivery devices have been developed. One of the

7

few examples of studies focused on nose to brain delivery in humans utilized the Vianase™ to

8

delivery insulin intranasally12. Vianase™ is an electronic atomizer device developed by Kurve

9

Technology® which consists of a nebulizer attached to a vortex chamber. Nebulized medication

10

particles move in a vortex in the vortex chamber and continue to exhibit this flow when leaving

11

the device98. This promotes deposition to the olfactory region to maximize transport to the

12

brain12.

13

During exhalation the soft palate, which connects the nasal cavity to the rest of the respiratory

14

tract, is closed off

15

which uses the patient’s own exhalation force to emit the dose from the device. Closure of the

16

soft palate ensures that none of the flowing powder can be deposited into the lungs. Djupesland

17

and Skretting compared the deposition of radiolabeled lactose from the Opt-Powder device to the

18

deposition of a radiolabeled liquid formulation from a conventional pump nasal spray in seven

19

subjects. They report approximately 18% of the of radiolabeled lactose powder from the Opt-

20

Powder deposited in the upper region of the nasal cavity while only about 2.4% of the liquid

21

from the spray was deposited in the same region97. An example of the deposition from the Opt-

22

Powder and the conventional nasal spray in one subject is presented in Figure 3. In addition to

23

exhalation, swallowing can also be used to close the soft palate during nasal administration.

. The Opt-Powder device by Optinose® is a bi-directional delivery device

AC C

EP

97

TE D

M AN U

SC

RI PT

1

24

ACCEPTED MANUSCRIPT

SipNose has developed a drinking actuated nasal device which similarly, enables delivery of

2

small particle aerosols without deposition in the lower airways.99 Impel Neuropharma has

3

developed a device to delivery either powder or liquids through an insufflation method similar to

4

that used by Optinose®, however, instead of using the patient’s own exhalation force the device

5

uses pressurized gas to emit the dose. Utilizing this device, Hoekman et al found significantly

6

higher deposition in the upper regions of the nasal tract while having significantly lower

7

deposition in the anterior region when tested 7 human subjects. 45% of the dose was deposited in

8

the upper nasal region compared to about 12% from a conventional nasal spray100. It is important

9

to note that the upper region defined in the study by Djupesland and Skretting was a much

12

SC

M AN U

TE D

11

smaller area than that defined by Hoekman et al., making them not readily comparable.

EP

10

RI PT

1

Figure 3. Estimated Deposition from Nasal Delivery Devices Based on In Vivo Imaging Studies.

14

Delivery from Impel Neuropharma’s POD device covers a large area of the nasal cavity

15

including the upper regions (a)100. The powder delivery from Optinose Bi-Directional™ powder

16

device reaches the upper regions of the nasal cavity(b)97, whereas the deposition from a

17

traditional nasal spray is mostly located in the vestibule and lower turbinate region(c)97.

AC C

13

18

25

ACCEPTED MANUSCRIPT

4. Conclusion

2

Many studies have attempted different formulation techniques to improve brain delivery by

3

direct nose-to-brain mechanisms. By utilizing mucoadhesive excipients in nasal formulations, it

4

is possible to increase the amount of medications delivered to the brain. While mucoadhesives

5

are effective at increasing brain concentrations, experiments combining their use with other

6

formulation techniques have produced even greater brain uptake. Using formulation

7

characteristics to increase the concentration and permeability, microemulsions and solid lipid

8

nanoparticles have positively influenced the concentrations given to the brain. Studies with

9

acetazolamide and matrix metalloproteinase-9 have shown that by taking advantage of what we

10

know about brain and nasal mucosal anatomy we can further improve drug delivery. Although

11

research of these pathways in humans is limited, current literature indicates that this may be

12

therapeutically advantageous in the future. Formulation composition appears to have a

13

significant effect on drug uptake into the brain. However, as not all formulation strategies have

14

shown to produce significant increases in brain delivery, there is a call for future research in

15

formulation design and standardization on in vitro and in vivo experimental conditions.

16

Formulations strategies alone are not enough to take advantage of this pathway for human drug

17

delivery. Novel devices are being developed which attempt to overcome the barriers of the nasal

18

cavity anatomy and target formulation deposition in the olfactory region of the nasal cavity. By

19

maximizing brain concentrations and limiting systemic exposure, this pathway offers the ability

20

to decrease systemic side effects while producing therapeutics effects that otherwise would not

21

be possible using other non-invasive routes of administration.

AC C

EP

TE D

M AN U

SC

RI PT

1

22

26

ACCEPTED MANUSCRIPT

AUTHOR INFORMATION

2

Author Contributions

3

The manuscript was written through contributions of all authors. All authors have given approval

4

to the final version of the manuscript.

5

REFERENCES

6

1.

and Approaches (Springer Science & Business Media, 2013).

9

Expert Consult - Online and Print, 6e 147–161 (Saunders, 2011). 3.

11

for drug delivery to the brain. Brain Res. 692, 278–282 (1995). 4.

13 14

(1997). 5.

15 16

6.

Graeme F Woodworth, G. P. D. Emerging Insights into Barriers to Effective Brain Tumor Therapeutics. Front. Oncol. 4, 126 (2014).

7.

19 20

Shingaki, T. et al. Transnasal Delivery of Methotrexate to Brain Tumors in Rats: A New Strategy for Brain Tumor Chemotherapy. Mol. Pharm. 7, 1561–1568 (2010).

17 18

Frey, W. H. et al. Delivery of 125I-NGF to the Brain via the Olfactory Route. Drug Deliv. 4, 87–92

TE D

12

Thorne, R. G., Emory, C. R., Ala, T. A. & Frey II, W. H. Quantitative analysis of the olfactory pathway

EP

10

Nimjee, S., Grant, G., Winn, H. R. & Janigro, D. in Youmans Neurological Surgery, 4-Volume Set:

M AN U

2.

AC C

8

Lockhead, J. & Thorne, R. G. in Drug Delivery to the Brain: Physiological Concepts, Methodologies

SC

7

RI PT

1

S. Hersh, D. et al. Evolving Drug Delivery Strategies to Overcome the Blood Brain Barrier. Curr. Pharm. Des. 22, 1177–1193 (2016).

8.

Pardeshi, C. V. & Belgamwar, V. S. Direct nose to brain drug delivery via integrated nerve pathways

21

bypassing the blood–brain barrier: an excellent platform for brain targeting. Expert Opin. Drug

22

Deliv. 10, 957–972 (2013).

27

ACCEPTED MANUSCRIPT

1

9.

Becker, Y. HSV-1 brain infection by the olfactory nerve route and virus latency and reactivation

2

may cause learning and behavioral deficiencies and violence in children and adults: A point of

3

view. Virus Genes 10, 217–226 (1995).

5

of drugs. Expert Opin. Drug Deliv. 5, 1159–1168 (2008). 11.

7

intranasal administration in humans. Sci. Rep. 3, (2013). 12.

9 10

Craft S, Baker LD, Montine TJ & et al. Intranasal insulin therapy for alzheimer disease and amnestic mild cognitive impairment: A pilot clinical trial. Arch. Neurol. 69, 29–38 (2012).

13.

11 12

SC

8

Striepens, N. et al. Elevated cerebrospinal fluid and blood concentrations of oxytocin following its

M AN U

6

Wu, H., Hu, K. & Jiang, X. From nose to brain: understanding transport capacity and transport rate

RI PT

10.

Dhuria, S. V., Hanson, L. R. & Frey, W. H. Intranasal delivery to the central nervous system: Mechanisms and experimental considerations. J. Pharm. Sci. 99, 1654–1673 (2010).

14.

13

Lochhead, J. J. & Thorne, R. G. Intranasal delivery of biologics to the central nervous system. Adv. Drug Deliv. Rev. 64, 614–628 (2012).

TE D

4

14

15.

Baker, H. & Genter, M. B. in Handbook of Olfaction and Gustation 549–574 (CRC Press, 2003).

15

16.

Shingaki, T. et al. The transnasal delivery of 5-fluorouracil to the rat brain is enhanced by acetazolamide (the inhibitor of the secretion of cerebrospinal fluid). Int. J. Pharm. 377, 85–91

17

(2009). 17.

Md, S. et al. Optimised nanoformulation of bromocriptine for direct nose-to-brain delivery:

AC C

18

EP

16

19

biodistribution, pharmacokinetic and dopamine estimation by ultra-HPLC/mass spectrometry

20

method. Expert Opin. Drug Deliv. 11, 827–842 (2014).

21

18.

Khan, M. S., Patil, K., Yeole, P. & Gaikwad, R. Brain targeting studies on buspirone hydrochloride

22

after intranasal administration of mucoadhesive formulation in rats. J. Pharm. Pharmacol. 61, 669–

23

675 (2009).

28

ACCEPTED MANUSCRIPT

19.

2 3

olfactory transport. J. Pharm. Pharmacol. 58, 63–72 (2006). 20.

4 5

Barakat, N. S., Omar, S. A. & Ahmed, A. a. E. Carbamazepine uptake into rat brain following intra-

Serralheiro, A., Alves, G., Fortuna, A. & Falcão, A. Intranasal administration of carbamazepine to mice: A direct delivery pathway for brain targeting. Eur. J. Pharm. Sci. 60, 32–39 (2014).

21.

RI PT

1

Wang, S., Chen, P., Zhang, L., Yang, C. & Zhai, G. Formulation and evaluation of microemulsionbased in situ ion-sensitive gelling systems for intranasal administration of curcumin. J. Drug Target.

7

20, 831–840 (2012). 22.

9 23.

11

Delivery of Doxepin. BioMed Res. Int. 2014, e847547 (2014). 24.

13 14

25.

26.

27.

23

Wang, F., Jiang, X. & Lu, W. Profiles of methotrexate in blood and CSF following intranasal and intravenous administration to rats. Int. J. Pharm. 263, 1–7 (2003).

28.

21 22

Hanson, L. R. et al. Intranasal delivery of growth differentiation factor 5 to the central nervous system. Drug Deliv. 19, 149–154 (2012).

19 20

Wang, X., He, H., Leng, W. & Tang, X. Evaluation of brain-targeting for the nasal delivery of estradiol by the microdialysis method. Int. J. Pharm. 317, 40–46 (2006).

17 18

Alam, M. I. et al. Pharmacoscintigraphic evaluation of potential of lipid nanocarriers for nose-tobrain delivery of antidepressant drug. Int. J. Pharm. 470, 99–106 (2014).

15 16

Naik, A. & Nair, H. Formulation and Evaluation of Thermosensitive Biogels for Nose to Brain

TE D

12

M AN U

safety evaluation. Int. J. Biol. Macromol. 67, 418–425 (2014).

EP

10

Bhavna et al. Donepezil nanosuspension intended for nose to brain targeting: In vitro and in vivo

AC C

8

SC

6

Westin, U. E., Boström, E., Gråsjö, J., Hammarlund-Udenaes, M. & Björk, E. Direct Nose-to-Brain Transfer of Morphine After Nasal Administration to Rats. Pharm. Res. 23, 565–572 (2006).

29.

Zhang, Q. et al. Preparation of nimodipine-loaded microemulsion for intranasal delivery and evaluation on the targeting efficiency to the brain. Int. J. Pharm. 275, 85–96 (2004).

29

ACCEPTED MANUSCRIPT

1

30.

Abdelbary, G. A. & Tadros, M. I. Brain targeting of olanzapine via intranasal delivery of core–shell

2

difunctional block copolymer mixed nanomicellar carriers: In vitro characterization, ex vivo

3

estimation of nasal toxicity and in vivo biodistribution studies. Int. J. Pharm. 452, 300–310 (2013). 31.

Seju, U., Kumar, A. & Sawant, K. K. Development and evaluation of olanzapine-loaded PLGA

RI PT

4 5

nanoparticles for nose-to-brain delivery: In vitro and in vivo studies. Acta Biomater. 7, 4169–4176

6

(2011). 32.

Kumar, M., Misra, A., Mishra, A. K., Mishra, P. & Pathak, K. Mucoadhesive nanoemulsion-based

SC

7

intranasal drug delivery system of olanzapine for brain targeting. J. Drug Target. 16, 806–814

9

(2008).

10

33.

M AN U

8

Patel, M. R., Patel, R. B., Bhatt, K. K., Patel, B. G. & Gaikwad, R. V. Paliperidone microemulsion for

11

nose-to-brain targeted drug delivery system: pharmacodynamic and pharmacokinetic evaluation.

12

Drug Deliv. 1–9 (2014). doi:10.3109/10717544.2014.914602 34.

14 15

Wang, D., Gao, Y. & Yun, L. Study on brain targeting of raltitrexed following intranasal

TE D

13

administration in rats. Cancer Chemother. Pharmacol. 57, 97–104 (2006). 35.

Ravi, P. R., Aditya, N., Patil, S. & Cherian, L. Nasal in-situ gels for delivery of rasagiline mesylate: improvement in bioavailability and brain localization. Drug Deliv. 1–8 (2013).

17

doi:10.3109/10717544.2013.860501 36.

Stevens, J., Ploeger, B. A., Graaf, P. H. van der, Danhof, M. & Lange, E. C. M. de. Systemic and

AC C

18

EP

16

19

Direct Nose-to-Brain Transport Pharmacokinetic Model for Remoxipride after Intravenous and

20

Intranasal Administration. Drug Metab. Dispos. 39, 2275–2282 (2011).

21

37.

22 23 24

Kumar, M. et al. Intranasal nanoemulsion based brain targeting drug delivery system of risperidone. Int. J. Pharm. 358, 285–291 (2008).

38.

Patel, S. et al. Brain targeting of risperidone-loaded solid lipid nanoparticles by intranasal route. J. Drug Target. 19, 468–474 (2011).

30

ACCEPTED MANUSCRIPT

1

39.

Khan, S., Patil, K., Bobade, N., Yeole, P. & Gaikwad, R. Formulation of intranasal mucoadhesive

2

temperature-mediated in situ gel containing ropinirole and evaluation of brain targeting efficiency

3

in rats. J. Drug Target. 18, 223–234 (2010).

5

delivery system of saquinavir mesylate for brain targeting. Drug Deliv. 21, 148–154 (2013). 41.

7 8

Pharm. Pharmacol. 59, 1199–1205 (2007). 42.

9

Jogani, V. V. Mp., Shah, P. J. Mp., Mishra, P., Mishra, A. K. & Misra, A. R. P. *. Intranasal Mucoadhesive Microemulsion of Tacrine to Improve Brain Targeting. Alzheimer Dis. Assoc. Disord.

10 11

Jogani, V. V., Shah, P. J., Mishra, P., Mishra, A. K. & Misra, A. R. Nose-to-brain delivery of tacrine. J.

SC

6

Mahajan, H. S., Mahajan, M. S., Nerkar, P. P. & Agrawal, A. Nanoemulsion-based intranasal drug

RI PT

40.

April. 2008 22, 116–124 (2008). 43.

M AN U

4

Banks, W. A., Morley, J. E., Niehoff, M. L. & Mattern, C. Delivery of testosterone to the brain by intranasal administration: Comparison to intravenous testosterone. J. Drug Target. 17, 91–97

13

(2009). 44.

15

of rats. Int. J. Pharm. 195, 197–205 (2000). 45.

17 18

Microparticles. Mol. Pharm. 11, 1550–1561 (2014). 46.

19 20

Dalpiaz, A. et al. Brain Uptake of a Zidovudine Prodrug after Nasal Administration of Solid Lipid

EP

16

Dahlin, M. & Björk, E. Nasal absorption of (S)-UH-301 and its transport into the cerebrospinal fluid

Jain, R., Nabar, S., Dandekar, P. & Patravale, V. Micellar Nanocarriers: Potential Nose-to-Brain

AC C

14

TE D

12

Delivery of Zolmitriptan as Novel Migraine Therapy. Pharm. Res. 27, 655–664 (2010). 47.

Brenneman, K. A. et al. Direct Olfactory Transport of Inhaled Manganese (54MnCl2) to the Rat

21

Brain: Toxicokinetic Investigations in a Unilateral Nasal Occlusion Model. Toxicol. Appl. Pharmacol.

22

169, 238–248 (2000).

31

ACCEPTED MANUSCRIPT

1

48.

Henriksson, J., Tallkvist, J. & Tjälve, H. Transport of Manganese via the Olfactory Pathway in Rats:

2

Dosage Dependency of the Uptake and Subcellular Distribution of the Metal in the Olfactory

3

Epithelium and the Brain. Toxicol. Appl. Pharmacol. 156, 119–128 (1999).

5

olfactory pathways in rats. Toxicol. Lett. 145, 19–27 (2003). 50.

7 8

following intranasal administration. Mol. Genet. Metab. 106, 131–134 (2012). 51.

9

Thorne, R. G., Pronk, G. J., Padmanabhan, V. & Frey II, W. H. Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal

10 11

Wolf, D. A. et al. Lysosomal enzyme can bypass the blood–brain barrier and reach the CNS

SC

6

Persson, E., Henriksson, J. & Tjälve, H. Uptake of cobalt from the nasal mucosa into the brain via

RI PT

49.

M AN U

4

administration. Neuroscience 127, 481–496 (2004). 52.

Appu, A. P., Arun, P., Krishnan, J. K. S., Moffett, J. R. & Namboodiri, A. M. A. Rapid intranasal delivery of chloramphenicol acetyltransferase in the active form to different brain regions as a

13

model for enzyme therapy in the CNS. J. Neurosci. Methods 259, 129–134 (2016).

14

53.

TE D

12

Kandimalla, K. K. & Donovan, M. D. Transport of hydroxyzine and triprolidine across bovine olfactory mucosa: Role of passive diffusion in the direct nose-to-brain uptake of small molecules.

16

Int. J. Pharm. 302, 133–144 (2005). 54.

18 19

administration to rats. Eur. J. Pharm. Sci. 14, 75–80 (2001). 55.

20 21

24

Krishnan, J. K. S. et al. Intranasal delivery of obidoxime to the brain prevents mortality and CNS damage from organophosphate poisoning. NeuroToxicology 53, 64–73 (2016).

56.

22 23

Dahlin, M., Jansson, B. & Björk, E. Levels of dopamine in blood and brain following nasal

AC C

17

EP

15

Mistry, A., Stolnik, S. & Illum, L. Nanoparticles for direct nose-to-brain delivery of drugs. Int. J. Pharm. 379, 146–157 (2009).

57.

Han, I.-K. et al. Enhanced brain targeting efficiency of intranasally administered plasmid DNA: an alternative route for brain gene therapy. J. Mol. Med. 85, 75–83 (2007).

32

ACCEPTED MANUSCRIPT

1

58.

Pietrowsky, R., Strüben, C., Mölle, M., Fehm, H. L. & Born, J. Brain potential changes after

2

intranasal vs. intravenous administration of vasopressin: evidence for a direct nose-brain pathway

3

for peptide effects in humans. Biol. Psychiatry 39, 332–340 (1996). 59.

5 6

Fehm, H. L. et al. The Melanocortin Melanocyte-Stimulating Hormone/Adrenocorticotropin4–10

RI PT

4

Decreases Body Fat in Humans. J. Clin. Endocrinol. Metab. 86, 1144–1148 (2001). 60.

Ruigrok, M. J. R. & de Lange, E. C. M. Emerging Insights for Translational Pharmacokinetic and Pharmacokinetic-Pharmacodynamic Studies: Towards Prediction of Nose-to-Brain Transport in

8

Humans. AAPS J. (2015). doi:10.1208/s12248-015-9724-x

SC

7

61.

Touitou, E. & Illum, L. Nasal drug delivery. Drug Deliv. Transl. Res. 3, 1–3 (2013).

10

62.

Nakamura, F., Ohta, R., Machida, Y. & Nagai, T. In vitro and in vivo nasal mucoadhesion of some

11

water-soluble polymers. Int. J. Pharm. 134, 173–181 (1996). 63.

13 14

Pennington, A. K., Ratcliffe, J. H., Wilson, C. G. & Hardy, J. G. The influence of solution viscosity on nasal spray deposition and clearance. Int. J. Pharm. 43, 221–224 (1988).

64.

TE D

12

M AN U

9

Charlton, S., Jones, N. S., Davis, S. S. & Illum, L. Distribution and clearance of bioadhesive formulations from the olfactory region in man: Effect of polymer type and nasal delivery device.

16

Eur. J. Pharm. Sci. 30, 295–302 (2007). 65.

18

Chaturvedi, M., Kumar, M. & Pathak, K. A review on mucoadhesive polymer used in nasal drug delivery system. J. Adv. Pharm. Technol. Res. 2, 215–222 (2011).

AC C

17

EP

15

19

66.

Illum, L. Is nose-to-brain transport of drugs in man a reality? J. Pharm. Pharmacol. 56, 3–17 (2004).

20

67.

Cai, Z. et al. Formulation and Evaluation of In Situ Gelling Systems for Intranasal Administration of

21 22 23

Gastrodin. AAPS PharmSciTech 12, 1102–1109 (2011). 68.

Illum, L. Nasal drug delivery—possibilities, problems and solutions. J. Controlled Release 87, 187– 198 (2003).

33

ACCEPTED MANUSCRIPT

1

69.

2 3

Gao, X. et al. Lectin-conjugated PEG–PLA nanoparticles: Preparation and brain delivery after intranasal administration. Biomaterials 27, 3482–3490 (2006).

70.

Gao, X. et al. Brain delivery of vasoactive intestinal peptide enhanced with the nanoparticles conjugated with wheat germ agglutinin following intranasal administration. J. Controlled Release

5

121, 156–167 (2007).

6

71.

RI PT

4

Liu, Q. et al. In vivo toxicity and immunogenicity of wheat germ agglutinin conjugated

poly(ethylene glycol)-poly(lactic acid) nanoparticles for intranasal delivery to the brain. Toxicol.

8

Appl. Pharmacol. 251, 79–84 (2011). 72.

Sharma, D. et al. Formulation and Optimization of Polymeric Nanoparticles for Intranasal Delivery

M AN U

9

SC

7

10

of Lorazepam Using Box-Behnken Design: In Vitro and In Vivo Evaluation. BioMed Res. Int. 2014,

11

e156010 (2014).

12

73.

Mistry, A., Stolnik, S. & Illum, L. Nose-to-Brain Delivery: Investigation of the Transport of Nanoparticles with Different Surface Characteristics and Sizes in Excised Porcine Olfactory

14

Epithelium. Mol. Pharm. 12, 2755–2766 (2015). 74.

16 17

Fazil, M. et al. Development and evaluation of rivastigmine loaded chitosan nanoparticles for brain targeting. Eur. J. Pharm. Sci. 47, 6–15 (2012).

75.

EP

15

TE D

13

Dhuria, S. V., Hanson, L. R. & Frey, W. H. Novel vasoconstrictor formulation to enhance intranasal targeting of neuropeptide therapeutics to the central nervous system. J. Pharmacol. Exp. Ther.

19

328, 312–320 (2009).

20

76.

AC C

18

Lochhead, J. J., Wolak, D. J., Pizzo, M. E. & Thorne, R. G. Rapid transport within cerebral

21

perivascular spaces underlies widespread tracer distribution in the brain after intranasal

22

administration. J. Cereb. Blood Flow Metab. 35, 371–381 (2015).

23 24

77.

Drejer, K. et al. Intranasal Administration of Insulin With Phospholipid as Absorption Enhancer: Pharmacokinetics in Normal Subjects. Diabet. Med. 9, 335–340 (1992).

34

ACCEPTED MANUSCRIPT

78.

2 3

enhancement by hydrophobic bile salts. Proc. Natl. Acad. Sci. 82, 7419–7423 (1985). 79.

4 5

Behl, C. R. et al. Optimization of systemic nasal drug delivery with pharmaceutical excipients. Adv. Drug Deliv. Rev. 29, 117–133 (1998).

80.

6

Arora, P., Sharma, S. & Garg, S. Permeability issues in nasal drug delivery. Drug Discov. Today 7, 967–975 (2002).

81.

Karasulu, E., Yavaşoğlu, A., Evrenşanal, Z., Uyanıkgil, Y. & Karasulu, H. Y. Permeation Studies and

SC

7

Gordon, G. S., Moses, A. C., Silver, R. D., Flier, J. S. & Carey, M. C. Nasal absorption of insulin:

RI PT

1

Histological Examination of Sheep Nasal Mucosa Following Administration of Different Nasal

9

Formulations with or without Absorption Enhancers. Drug Deliv. 15, 219–225 (2008).

10

82.

M AN U

8

Karasulu, H. Y., Şanal, Z. E., Sözer, S., Güneri, T. & Ertan, G. Permeation Studies of Indomethacin

11

from Different Emulsions for Nasal Delivery and Their Possible Anti-Inflammatory Effects. AAPS

12

PharmSciTech 9, 342–348 (2008).

14 15

Different Administration Routes in Mice. Int. J. Mol. Sci. 13, 14127–14135 (2012). 84.

16 17

Lu, Y. et al. Bioavailability and Brain-Targeting of Geniposide in Gardenia-Borneol Co-Compound by

TE D

83.

Jadhav, K. R., Shaikh, I. M., Ambade, K. W. & Kadam, V. J. Applications of Microemulsion Based Drug Delivery System. Curr. Drug Deliv. 3, 267–273 (2006).

85.

EP

13

Shah, B. M., Misra, M., Shishoo, C. J. & Padh, H. Nose to brain microemulsion-based drug delivery system of rivastigmine: formulation and ex-vivo characterization. Drug Deliv. 1–13 (2014).

19

doi:10.3109/10717544.2013.878857

20

86.

AC C

18

Hosny, K. M. & Hassan, A. H. Intranasal in situ gel loaded with saquinavir mesylate nanosized

21

microemulsion: Preparation, characterization, and in vivo evaluation. Int. J. Pharm. 475, 191–197

22

(2014).

35

ACCEPTED MANUSCRIPT

1

87.

Sood, S., Jain, K. & Gowthamarajan, K. Optimization of curcumin nanoemulsion for intranasal

2

delivery using design of experiment and its toxicity assessment. Colloids Surf. B Biointerfaces 113,

3

330–337 (2014). 88.

5 6

Montenegro, L. et al. In vitro evaluation of idebenone-loaded solid lipid nanoparticles for drug delivery to the brain. Drug Dev. Ind. Pharm. 37, 737–746 (2011).

89.

RI PT

4

Pardeshi, C. V., Rajput, P. V., Belgamwar, V. S., Tekade, A. R. & Surana, S. J. Novel surface modified solid lipid nanoparticles as intranasal carriers for ropinirole hydrochloride: application of factorial

8

design approach. Drug Deliv. 20, 47–56 (2013).

SC

7

90.

Clerico, D., To, W. & Lanza, D. in Handbook of Olfaction and Gustation 1–16 (CRC Press, 2003).

10

91.

Mygind, N. & Dahl, R. Anatomy, physiology and function of the nasal cavities in health and disease.

11 92.

13 93.

15 16

94.

95.

Cheng, Y. S. et al. Characterization of nasal spray pumps and deposition pattern in a replica of the human nasal airway. J. Aerosol Med. Off. J. Int. Soc. Aerosols Med. 14, 267–280 (2001).

96.

21 22

Hardy, J. G., Lee, S. W. & Wilson, C. G. Intranasal drug delivery by spray and drops. J. Pharm. Pharmacol. 37, 294–297 (1985).

19 20

Kublik, H. & Vidgren, M. T. Nasal delivery systems and their effect on deposition and absorption. Adv. Drug Deliv. Rev. 29, 157–177 (1998).

17 18

TE D

Gad, S. C.) 591–650 (Wiley-Interscience, 2008).

EP

14

Thomas, C. & Ahsan, F. in Pharmaceutical Manufacturing Handbook: Production and Processes (ed.

AC C

12

Adv. Drug Deliv. Rev. 29, 3–12 (1998).

M AN U

9

Foo, M. Y., Cheng, Y.-S., Su, W.-C. & Donovan, M. D. The Influence of Spray Properties on Intranasal Deposition. J. Aerosol Med. 20, 495–508 (2007).

97.

Djupesland, P. G. & Skretting, A. Nasal deposition and clearance in man: comparison of a

23

bidirectional powder device and a traditional liquid spray pump. J. Aerosol Med. Pulm. Drug Deliv.

24

25, 280–289 (2012).

36

ACCEPTED MANUSCRIPT

1

98.

Giroux, M. Particle dispersion device for nasal delivery. (2007).

2

99.

Shahaf, D. & HADASH, J. Nasal delivery device. (2016).

3

100. Hoekman, J., Brunelle, A., HIte, M., Kim, P. & Fuller, C. SPECT Imaging of Direct Nose-to-Brain Transfer of MAG-3 in Man. (2013).

RI PT

4 5 6

SC

7

AC C

EP

TE D

M AN U

8

37