Download Quantification of the Distribution of MP29-02 (Dymista

Quantification of the Distribution of MP29-02 (Dymista-Azelastine HCl/Fluticasone Propionate Nasal Spray)
in an Anatomical Model of the Human Nasal Cavity
Alexander D. D’Addio, PhD1; Nancy M. Ruiz, MD1; Michael J. Mayer, PhD 2; William Berger, MD 3; Eli O. Meltzer, MD 4
1
Meda Pharmaceuticals Inc., Somerset, NJ; 2Next Breath, LLC, Baltimore, MD; 3Allergy and Asthma Associates of Southern California, Mission Viejo, CA; 4Allergy and Asthma Medical Group and Research Center, San Diego, CA
The nasal cast used was sourced from Diffusion Technique Francaise (DTF). The
Aptar/DTF Cast is divided into sections (four total sections) allowing for discrete
analysis of each region of the nasal vault (dripping if it occurs, nose/nasal valve,
turbinates, rear portion of the turbinates, and nasopharynx). Protocol-specified
set up and experimental parameters included:
● Cast tilted 15°
● Flow rate of 15 L/min was applied to the cast (as measured from the nostril
with the opposite nostril plugged with Parafilm)
● Nasal spray was angled slightly away from the septum and parallel to the nostril
(simulating when the orientation of the nasal spray from the package insert)
● For sequential administration of AZE and either FP or Flonase, there was a
1 minute waiting period between actuations with the flow off
● After administration of nasal spray to the cast, the sections of the casts were
placed in a plastic zipper freezer bag. If leakage from the nostril occurred, it
was captured in a separate zipper bag. The posterior filter was placed in a
separate zipper bag.
● Each section was then washed with a specified volume of diluent (70:30
water/acetonitrile) inside the zipper bag
● The solution was then transferred to brown bottles for storage
● Samples were analyzed by HPLC
Results: A single spray of MP29-02 showed a uniform distribution of
close to 100% of applied drug within the nose/nasal valve and
turbinates (first 2 sections of the cast); the average % AZE was 61.4%
in section 1 and 38.6% in section 2 and the average % FP was 65.4%
and 34.6% in sections 1 and 2, respectively. In comparison, single
sprays of the individual agents showed uneven distribution of AZE and
FP and a substantial amount of dripping from sequential administration.
Conclusions: Application of MP29-02 in a single spray provided more
uniform distribution and greater retention in the nasal cavity than
sequential sprays of the individual components, potentially allowing
for better local absorption of medication.
Distribution of MP29-02 (Dymista) as a Single Spray
Nasal Cast Location
% AZE
per Section
% FP
per Section
Range of % AZE
per Section
Range of % FP
per Section
75
50
Anterior Dripping
0.0
0.0
0.0
0.0
Section 1
61.4
65.4
53.7 – 65.8
55.5 – 71.8
Section 2
38.6
34.6
34.2 – 46.3
28.2 – 44.5
Section 3
0.0
0.0
0.0
0.0
Section 4
0.0
0.0
0.0
0.0
Average % Recovery Total
98.7
87.3
95.8 – 104.2
83.4 – 91.7
●
●
38.6
Range of % AZE
per Section
Range of % FP
per Section
Anterior Dripping
16.9
6.6
7.7 – 31.9
2.7 – 6.7
Aptar/DTF Cast
Section 1
47.3
68.3
38.6 – 58.2
52.4 – 76.4
Four sections of Aptar/DTF Nasal Cast
Section 2
35.8
25.1
25.7 – 44.8
16.9 – 47.6
Section 3
0.0*
0.0*
0.0†
0.0†
Section 4
0.0
0.0
0.0
0.0
Average % Recovery Total
80.1
95.2
72.7 – 90.8
90.9 – 99.0
Nasal Cast Location
●
●
1
Turbinates
Rear of
Turbinates
4
Assembled Aptar/DTF Nasal Cast
Nasal Cast Location
% FP
per Section
Range of % AZE
per Section
Range of % FP
per Section
Anterior Dripping
25.7
7.9
6.6 – 39.2
12.8†
Section 1
41.7
66.2
27.2 – 54.2
52.4 – 78.9
Section 2
33.5
28.5
24.2 – 52.6
15.2 – 47.6
Section 3
3.4*
0.0*
0.0 – 20.2
Objective
Section 4
0.0*
0.0*
0.0
0.0†
Average % Recovery Total
77.4
82.1
63.2 – 91.3
70.2 – 94.5
The objective of this study was to evaluate nasal cast deposition of
MP29-02 (Dymista Nasal Spray) compared to sequential administration
of AZE followed by either generic FP or Flonase.
*Drug detected but below the linearity concentration in some replicates; †below linearity
●
The nasal cast is modeled on a single healthy, adult, Caucasian male
MP29-02 as a single spray was the
only application that did not show
dripping from the nose/nostril section
of the cast
0
0
0
0
Anterior
Dripping
1
2
0
0
3
●
MP29-02 as a single spray
demonstrated uniform distribution of
the two components
●
In contrast, the AZE and FP
components administered sequentially
showed as much as 25% dripping
from the anterior portion of the
nose/nostril section of the cast
●
In addition, the AZE and FP
components administered sequentially
showed uneven distribution within
the cast
●
These results suggest that MP29-02
as a single spray provided uniform
distribution of the two drug
components, targeting the nose/nostril
and anterior portion of the turbinates
with no loss of drug through dripping
from the nose/nostril section of
the cast
●
In patients, there may be greater
retention in the nasal mucosa with
MP29-02 than with the components
administered sequentially
0
4
Cast Section
75
AZE
68.3
50
FP
47.3
35.8
25
25.1
16.9
6.6
0
Anterior
Dripping
0
1
2
0
0
3
0
4
Cast Section
Distribution of AZE (generic) and FP (generic) Administered Sequentially
% AZE
per Section
0.0†
●
●
34.6
Administration of AZE (generic) and Flonase sequentially resulted in uneven distribution of the two components relative to each other in the nose/nostril and anterior turbinate sections of the cast
Dripping from the anterior of the nose/nostril section of the cast was observed for both components
Nasopharynx
2
3
Cast Section
Conclusions
Distribution of AZE (generic) and FP (Flonase) Administered Sequentially
% FP
per Section
Nose/Nostril
FP
25
*Drug detected but below the linearity concentration in some replicates; †below linearity
Since the introduction of MP29-02 Nasal Spray in the US in September
2012, questions have arisen regarding the therapeutic equivalence of
using the two components sequentially as compared to the single spray
MP29-02 product. A previous series of experiments using an
anatomical model of the human nasal cavity demonstrated the
distribution and retention of AZE and FP administered either
sequentially or as a single spray (Dymista). These qualitative
assessments indicated that administration of MP29-02 as a single
spray had superior retention and distribution characteristics compared
to sequential administration of the two components. When
administered sequentially, AZE and FP both showed dripping from the
nostrils and runoff toward the nasopharynx.
AZE
65.4
Administration of MP29-02 as a single spray resulted in even distribution of the two components in the nose/nostril and anterior turbinate sections of the cast
Dripping was not detected from the anterior portion of the nose/nostril section of the cast
% AZE
per Section
Background
61.4
●
75
AZE
66.2
Average (%)
Methods: The cast was divided into 4 sections from anterior to posterior
of the cast. A single spray of MP29-02 (0.137 mL [137 mcg of
azelastine/50 mcg of fluticasone propionate]) or sequential single
sprays of azelastine (0.137 mL) followed by generic fluticasone
propionate or Flonase nasal spray (0.100 mL) were manually actuated
into the model. A vacuum (15 L/min) was applied during actuation to
simulate nasal inhalation. Following extraction from the nasal cast,
HPLC was used to quantify drug deposition on the different sections of
the cast. Each experiment was repeated three times.
Results
Average (%)
Materials and Methods
Rationale: In vitro evaluations using an anatomical model of the human
nasal cavity quantified the distribution of MP29-02 (a novel intranasal
formulation of azelastine hyrochloride [AZE] and fluticasone
propionate [FP] in an advanced delivery system) administered as a
single nasal spray (Dymista) compared to sequential sprays of
marketed azelastine and either Flonase or generic fluticasone.
Average (%)
Abstract
FP
50
41.7
33.5
25
0
25.7
28.5
7.9
Anterior
Dripping
3.4
1
2
0
0
3
0
4
Cast Section
Administration of AZE (generic) and FP (generic) sequentially resulted in uneven distribution of the two components relative to each other in the nose/nostril and anterior turbinate sections of the cast
Dripping from the anterior of the nose/nostril section of the cast was observed for both components
Study funded by Meda Pharmaceuticals Inc., Somerset, NJ, USA.