Personalized Medicine in Nasal Delivery - American Chemical Society

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Personalized medicine in nasal delivery: the use of patient-specific administration parameters to improve nasal drug targeting using 3D printed nasal replica casts Zachary N. Warnken, Hugh D. C. Smyth, Daniel A. Davis, Steve Weitman, John G. Kuhn, and Robert O. Williams Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.7b00702 • Publication Date (Web): 27 Feb 2018 Downloaded from http://pubs.acs.org on February 28, 2018

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Molecular Pharmaceutics

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Personalized medicine in nasal delivery: the use of patient-

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specific administration parameters to improve nasal drug

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targeting using 3D printed nasal replica casts

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Zachary N. Warnken (1), Hugh D.C. Smyth*1(1), Daniel A. Davis (1), Steve Weitman (2), John G.

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Kuhn (3) and Robert O. Williams III2*(1)

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(1) Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, University

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of Texas at Austin, Austin, TX 78712

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(2) Institute for Drug Development, Cancer Therapy and Research Center (CTRC), University of

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Texas Health San Antonio, 7979 Wurzbach Dr., San Antonio, TX 78229, USA

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

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TX 78712

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Abstract

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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)

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Molecular Pharmaceutics 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Effective targeting of nasal spray deposition could improve local, systemic, and CNS drug delivery,

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however, this has proven to be difficult due anatomical features of the nasal cavity including the nasal

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valve and turbinate structures. Furthermore, nasal cavity geometries and dimensions vary between

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individuals based on differences in their age, gender and ethnicity. The effect of patient-specific

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administration parameters was evaluated for their ability to overcome the barriers to targeted nasal

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drug delivery.

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The nasal spray deposition was evaluated in ten 3D printed nasal cavity replicas developed based on the

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CT-scans of five pediatric and five adult subjects. Cromolyn sodium nasal solution, USP modified with

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varying concentrations of hypromellose was utilized as a model nasal spray to evaluate the deposition

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pattern from formulations producing a variety of plume angles. A central composite design of

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experiments was implemented using the formulation with the narrowest plume angle to determine the

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patient-specific angle for targeting the turbinate region in each individual.

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The use of the patient-specific angle with this formulation significantly increased the turbinate

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deposition efficiency compared to that found for all subjects using an administration angle of 30o,

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around 90% compared to about 73%. Generally, we found turbinate deposition increased with

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decreases in the administration angle. Deposition to the upper regions of the replica was poor with any

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formulation or administration angle tested.

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Effective turbinate targeting of nasal sprays can be accomplished with the use of patient-specific

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administration parameters in individuals. Further research is required to see if these parameters can be

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device-controlled for patients and if other regions can be effectively targeted with other nasal devices.


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Keywords

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nasal drug delivery, personalized medicine, nasal spray, spray angle, intranasal administration,

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deposition pattern

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Introduction

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Targeting nasal spray deposition in the nasal cavity has been a long-standing issue but could significantly

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improve local, systemic, and CNS delivery via this route. A major obstacle for effective targeting of nasal

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deposition is the anatomy of the nasal cavity itself. Nasal cavity geometries can have significant

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variation between individuals based on factors such as age, gender and ethnicity. Given this variation, it

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is unclear whether specific administration angles, spray formulations, and actuation parameters, based

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on personalized or patient specific parameters may give rise to improved targeting within the nasal

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cavity. This study evaluates the use of patient-specific administration angles on targeting deposition

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within the nasal cavity and variability between individual subjects.



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Drug administration by the nasal route can lead to improved local, systemic and central nervous system

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delivery. The relatively high surface area, vascularization, and ability to mitigate the first-pass effect

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make the nasal route an effective route of delivery for certain medications intended for systemic

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delivery. Furthermore, the pathways for drugs to be directly transported from the nasal cavity to the

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brain without crossing the blood-brain barrier may overcome the limitations of other routes of delivery.

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The regions of interest within the nasal cavity for local and systemic delivery versus central nervous

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system delivery are different and therefore can be enhanced by selectively targeting the drug to its

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preferred site. The nasal mucosa located in the turbinate region of the nasal cavity is richly vascularized

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with a relatively low barrier to drug permeation making it a relevant target for systemic drug delivery1-3.

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This mucosa is often referred to as the respiratory region of the nasal cavity. The olfactory region of the

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nasal cavity uniquely provides direct contact of neurons with the external environment, which allows

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drugs to be directly transported to the brain after targeting intranasal delivery to this region compared

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to more diffuse nasal delivery4-6. However, targeting of the turbinates and the olfactory region is

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hindered by the nasal valve, which is the region of highest airflow resistance located in the anterior

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portion of the nasal cavity7.

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To study nasal deposition mechanisms, several in vitro tests have been developed using nasal cavity

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replicate models based on the nasal cavities of various individuals. The nasal cavity replicate model is a

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physical model designed to reflect the anatomical features of the human nasal cavity. The use of these

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models allows investigators to study drug deposition when systematically controlling individual aspects

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of nasal delivery, such as differences in inspiratory airflow rates, particles sizes, and nasal spray

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velocities and plume angles 8-10. The development of the nasal cavity replicas has often been derived

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from medical images such as CT-scans and MRI images providing an accurate representation of the nasal

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cavity. For this reason, we chose to study nasal deposition using nasal replicate models based on CT-

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scans that were manufactured by 3D-printing, however, instead of limiting our results to the findings 4 ACS Paragon Plus Environment

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from a single nasal replicate model, we have developed ten models based on different individuals

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including pediatric and adult subjects. We utilized multiple casts representing different patients in order

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to study patient-specific drug delivery as well as the variability in deposition patterns between

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individuals with different nasal geometries.

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Targeting nasal deposition to a specific region of the nasal cavity has been the focus of several previous

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studies, but they are limited by the lack of testing in different nasal cavity anatomies. Spray plumes with

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varying characteristics can be developed by changing nasal spray formulations, actuation parameters,

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and devices and this allows the investigation of spray deposition 11, 12. The influence that differing spray

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characteristics have on nasal deposition patterns has been reported by Cheng et al.13 Cheng et al.

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concluded that narrow plume angles and smaller droplets promote deposition to the turbinate

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regions13. Foo et al. further supported turbinate targeting by nasal sprays with narrow plume geometry

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angles. However, this was only found to hold true at particular angles of administration10. Both Cheng et

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al. and Foo et al. were limited to a nasal cast replica from a single individual. Guo et al. studied nasal

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spray deposition patterns in a separate single nasal cast reproduced from a human cadaver and found,

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to the contrary, that a wider plume angle enhanced turbinate targeting14. These conflicting findings

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from nasal casts developed from different individuals supports the need for further research using

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different nasal cavities. One aspect of targeted nasal delivery that has not been widely reported is the

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influence of the variability between different individual’s nasal cavity geometries on resulting outcomes.

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Swift et al. studied the deposition of particles in an adult and a child nasal replica cast and found

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differences in the deposition efficiency in the adult compared to the child15. The dimensions of the nasal

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cavity increase with age and are on average larger in adult males compared to females16. Additionally,

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changes in nasal deposition efficiencies can be influenced by the ethnicity of the subject17. All of these

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factors, gender, age, and ethnicity, may influence the deposition patterns from targeting nasal drug

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delivery systems. One method reported by Liu et al. to address the limitations of studying nasal 5 ACS Paragon Plus Environment


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deposition in a cast developed from a single individual was to standardize the nasal cavity geometry by

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averaging several subject’s nasal cavities18. However, the use of an average nasal cavity hides whether

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or not targeting is preferred or hindered in a particular group of subjects.

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The purpose of this study was to determine if optimization of the nasal deposition to the turbinates in

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each individual would result in an overall higher targeting efficiency with decreased variability. The

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decision to focus the study towards targeting the deposition to the turbinate region opposed to the

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upper region of the nasal cavity came from results discussed in detail below, showing poor upper region

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deposition from the tested nasal sprays regardless of the admininstration angle or formulation tested.

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We hypothesize that by determing the patient-specifc angle that produced the highest turbinate

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deposition efficiency, the average deposition in this region of interest would be improved compared to

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all individuals being limited to the same admininstration angle. Firstly, to assess the targeting and

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variability of nasal spray deposition, five pediatric and five adult nasal replica casts were developed and

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used for deposition experiments with each individual cast receiving the same actuation parameters.

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Cromolyn sodium was selected as the model drug in the study to quantitate deposition within the nasal

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cavity, since it is a solution nasal spray product indicated for children and adults ages 2 years and older.

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Pediatric, as defined in this study, means any subject less than the age of 18 years.

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Materials and Methods

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Cromolyn Sodium (> 98% purity) was purchased from Letco Medical (Decatur, USA). Cromolyn sodium

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nasal solution, USP (Bausch and Lomb, Tampa, USA) was purchased from 38th Street Pharmacy (Austin,

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USA). Hydroxypropyl methylcellulose E4M was kindly donated by The Dow Chemical Company (Midland,

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MI). Disodium edetate dihydrate and benzalkonium chloride 50% solution were purchased from Sigma-

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Aldrich (St. Louis, USA).

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Nasal replica casts 6 ACS Paragon Plus Environment

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Ten anatomically accurate nasal models were developed based on anonymized CT-Scans obtained from

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The University of Texas Health San Antonio. The University of Texas Health San Antonio Institutional

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Review Board determined that approval was not required for the following study since it was not

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considered as human research. Nasal models were developed by segmenting the nasal cavity from the

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CT-scans in 3D Slicer (http://www.slicer.org) according to automated and manual techniques to

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accurately convert the coronal cross-sections of the CT-scan into a 3D model19. The 3D model was

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printed by W. M. Keck Center for 3D innovation (El Paso, USA) using a Viper™ HA SLA® system (3D

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Systems Corp., Valencia, USA) with build layer thickness of 0.004 inches and resolution of 0.010 inches

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using Somos® Watershed XC 11122 (DSM Somos®, Elgin, USA) as the material. Information available for

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each cast including age, gender, and geometric parameters are reported in Table 1. The measurements

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used to depict the geometric parameters of the nasal cast replicas is presented in Figure 1. The

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minimum cross-section area was determined using Fiji (https://imagej.net/Fiji)21, by calculating the nasal

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cavity area in each slice of the nasal cavity and selecting the minimum area value.

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Table 1. Characteristics of the nasal replica casts included in this study

Cast

Age

Gender

Areamin (mm2)

Lengthn-t (mm)

C1

12

Female

258.3

75.9

C2

7

Female

114.0

59.2

C3

7

Female

217.2

59.8

C4

9

Female

173.5

63.6

C5

14

Female

299.2

69.0

C6

48

Male

249.2

88.0

C7

33

Male

279.3

86.7

C8

44

Female

218.7

80.7

C9

48

Male

249.3

86.0

C10

31

Female

213.2

78.2

Pediatric (n=5)

Adult(n=5)

Age (yrs.)

9.8(3.1)

40.8(8.2)

Areamin (mm2)

212.4 (72.2)

242.0(26.8) 7 ACS Paragon Plus Environment


Lengthn-t (mm) 134 135 136

65.5 (7.0)

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83.9 (4.2)

Areamin= minimum coronal cross-section area; Lengthn-t= length from nostrils to the end of the turbinates Averages presented as mean (standard deviation)

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Figure 1. An example of the nasal geometry measurements obtained to compare between the 10 nasal casts. The length of the nasal cavity (A) and the minimum coronal cross-section area (B).

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In order to quantitate the drug deposition in different regions of the nasal casts, they were each divided

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into five separate parts based on anatomy (Figure 2). The anterior portion of the nasal cavity included

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the vestibule and the nasal valve area and was defined as the region from the beginning of the nostrils

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to the start of the inferior turbinate. The nasopharynx region, located after the turbinates, was modified

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to fit tubing to connect the cast to a vacuum pump, allowing airflow through the nasal replica casts. The

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turbinate region was divided into three sections, the upper, middle and lower sections. The upper

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section of the turbinates included a large part of the superior turbinates and the region associated with

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olfaction. The middle and lower turbinate regions were then sliced such that they could be accurately

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printed without loose artifacts not connected to the cast divisions. Pins were placed on each part to

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ensure proper alignment of the five separate parts.


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Figure 2. An illustrative example of the anatomically correct nasal cast. Nasal cast models were developed based on CT-scans of patients (left) followed by 3D printing (right). The casts were segmented into five different sections (A=anterior, U=upper turbinate region, M=middle turbinate region, L= lower turbinate region, N=nasopharynx) to quantitate the deposition pattern within the nasal cavity.

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Preparation of cromolyn sodium nasal spray formulations

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Five aqueous nasal spray formulations were tested in 95.5 µL VP7 spray devices (Aptar Pharma, Le

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Vaudreuil, France) with increasing hypromellose content. Cromolyn sodium nasal solution was

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transferred from its original device to a VP7 spray device. Formulations with hypromellose were

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prepared by dissolving disodium edetate, and benzalkonium chloride in a solution of either 0.1%, 0.2%,

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0.4% or 0.8% hypromellose E4M followed by dissolution of cromolyn sodium at a concentration of 40

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mg/mL.

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Characterization of cromolyn sodium nasal spray formulations

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Nasal solution viscosity was measured in an AR-G2 rheometer (TA instruments, New Castle, USA) using

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cone-plate geometry with radius of 40 mm and angle of 1o 59’31” operated in continuous flow mode



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with shear rates from 1 s-1 to 50 s-1 at 20oC. The viscosity of each formulation was tested three times.

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The droplet size from the sprays was measured with a Malvern Spraytec® (Malvern Instruments,

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Malvern, UK). The spray device tip was placed at 4.5 cm below the center of the laser beam and

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actuation was performed using a MightyRunt automatic actuator (InnovaSystems, Inc., Moorestown,

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USA). The selection of the actuation settings was chosen based on average actuation parameters for

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adults reported by Doughty et al.20 The actuation force was 5.8 kg, the force rise time was 0.3 seconds

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with a hold time of 0.1 seconds, and the force fall time was 0.3 secs. The droplet size was taken as the

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average of three separate sprays. Spray actuation was performed in a compartment with walls lined

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with black-flocked paper (Thorlabs, Inc., Austin, USA). The same actuation parameters used for the

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droplet size analysis were used for the plume geometry angle measurements. The plume was visualized

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using a laser sheet aligned at the center of the spray device. The emitted plumes were captured using a

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camera at around 350 frames/second. Image analysis of the plume and curve fitting measurements

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were performed using Fiji21. All of the captured frames including the plume were compiled together and

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then processed in the same manner to define the boundaries of the plumes accurately. The boundaries

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of the plumes were output as Cartesian coordinates, and the left and right boundary points were

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separately fit to a linear curve. The plume geometry was determined by calculating the angle formed

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between the two curves based on the slopes of the two lines. The plume geometry angle was measured

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five times for each formulation.

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Deposition with the nasal replica casts

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Actuation of the nasal sprays in the nasal casts was performed with the same actuation settings as

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described in the characterization of cromolyn sodium nasal formulations method section. The nasal

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sprays were inserted into the nasal casts with an insertion depth of 5 mm. The nasal casts were

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maintained upright without any forward or backward tilting for each of the experiments. The angle of

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the nasal spray was controlled by adjusting the angle of the automated actuator with the use of a 360o 10 ACS Paragon Plus Environment

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vice (PanaVise®, Reno, USA). In order to test the effect of inspiratory airflow on the deposition of the

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spray within the nasal cavity, the casts were assembled and attached to a vacuum pump, which drew air

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at 0, 10 or 60 L/min through the casts and was performed with the commercial cromolyn sodium nasal

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formulation. Differences in deposition based on nasal spray formulation were studied at a nasal spray

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actuation angle of 60o from horizontal in the sagittal plane and 0o in the coronal plane with one spray in

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each nostril and without nasal airflow. The effect of nasal administration angle on the deposition within

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the casts was assessed with the 0.8% hypromellose E4M cromolyn sodium nasal solution formulation at

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an angle of 30, 45, 60 and 75 degrees from horizontal in the sagittal plane without airflow. The coronal

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angle was maintained at 0o for these experiments.

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The patient-specific angle for each cast was determined by using a central composite design of

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experiments. Each of the experiments in the design was tested with the 0.8% hypromellose E4M

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cromolyn sodium nasal solution and with a single actuation in the left nostril of each cast at each

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experimental condition. The output variable measured was the percent of cromolyn sodium detected in

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the turbinate region. The inputs studied were the coronal plane and sagittal plane angles of

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administration of the nasal spray device (Table 2). The range of sagittal plane angles tested in each cast

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was selected based upon the angle associated with the highest turbinate efficiency found in the

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previous experiments testing the effect of administration angle on deposition. The central composite

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design was developed with an axial value that allowed the design to be rotatable and contained three

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central points. Central composite designs are a form of a response-surface design and allows estimation

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of curvature by the addition of axial points, often selected past the boundaries of the experiment. The

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matrix of the generated central composite design is depicted in Table 3. The statistical design of

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experiment was generated and analyzed by standard least squares regression using JMP® Pro 13 (SAS

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Institute, Inc., Cary, USA). The predicted angle for each cast that maximized the turbinate deposition

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efficiency was tested and considered the patient-specific angle. 11 ACS Paragon Plus Environment


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Table 2. Independent factor ranges tested in central composite design of experiments

X Cast C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 220 221 222 223

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o

Coronal angle range 0-20 0-20 0-20 0-20 0-20 0-20 0-20 0-20 0-20 0-20

Y

o

Sagittal angle range 30 - 45 30 - 45 35-50 35-50 30 - 45 30 - 45 35-50 35-50 35-50 35-50

Table 3. Example matrix of the central composite design experimental run for one of the nasal replica casts Run number Pattern Sagittal angle Coronal angle 1 -30 0 2 -+ 30 20 3 +45 0 4 ++ 45 20 5 a0 26.9 10 6 A0 48.1 10 7 0a 37.5 -4.1 8 0A 37.5 24.1 9 00 37.5 10 10 00 37.5 10 11 00 37.5 10

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Quantification of the cromolyn sodium deposition within the nasal casts was accomplished by

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disassembling the casts into their five individual parts, and then washing each part with five mL of 12 ACS Paragon Plus Environment

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deionized water. The concentration of cromolyn sodium from the obtained wash was analyzed by UV

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absorbance at a wavelength of 326 nm. The limit of quantification of cromolyn sodium was 6.25 µg/mL,

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which corresponds to 0.164% of a single actuation. The percentage of cromolyn sodium deposited in

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the turbinate region was calculated from the addition of the amount measured in the upper (U, Figure

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2), middle (M, Figure 2) and lower turbinate (L, Figure 2) regions divided by the total amount of

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cromolyn sodium measured.

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Statistical analysis

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Statistical analysis of the results was performed in JMP® Pro 13. Significant results between multiple

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groups were performed by ANOVA when no differences in variation were apparent. Otherwise, Welch’s

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ANOVA test was used. Multiple comparison’s tests used included Tukey-Kramer method for comparing

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all means or Dunnett’s test when comparing against a control. P-value of less than 0.05 was considered

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significant for all statistical tests. Data are presented as the mean ± the standard deviation. Error bars in

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the figures depict the standard deviation.

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Results

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Characterization of nasal formulations developed using different hypromellose E4M concentrations

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The resulting viscosities of the cromolyn sodium nasal spray formulations with increasing content of

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hypromellose E4M is presented in Figure 3. As the amount of hypromellose E4M increased, so did the

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resulting viscosity range, from 1 cP to about 53 cP. The formulations behaved as Newtonian liquids

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across the tested shear rates from 0-50 s-1 as evident by a linear increase in shear stress (data not

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shown).

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Figure 3. Characterization of nasal spray formulations and spray performance from nasal sprays with increasing hypromellose content. Values presented as the mean ± the standard deviation.

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The increase in viscosity resulted in a respective increase in the measured droplet size and a decrease in

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the plume angle. The Dv50 is presented in Figure 3; similar trends were observed for the Dv10 and Dv90

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of the droplet size distributions (data not shown). Particle size analysis results for the 0.4% hypromellose

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and 0.8% hypromellose formulations are presented in Figure 3. These measurements were obtained

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using laser diffraction analysis and are limited by the observation that the resulting plume was a stream

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rather than a diffuse plume of droplets.

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The increase in viscosity resulted in narrower plume angles ranging from about 48o to 24o. The plume

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geometry angle results from five individual sprays are presented in Figure 3, alongside an illustrative

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example of the analyzed nasal spray plume for each formulation. Comparison of the resulting plume

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geometry angles by ANOVA with posthoc Tukey-Kramer method test indicated that all plumes were

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significantly different (p-value

Personalized Medicine in Nasal Delivery - American Chemical Society

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