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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.