DEVELOPMENT OF CICLESONIDE 60 ACTUATION HFA p MDIs

DEVELOPMENT OF CICLESONIDE 60 ACTUATION HFA p. MDIs TO MATCH THE PHARMACEUTICAL PERFORMANCE OF THE 120 ACTUATION PRODUCT USING SLEEVED CAN (CAN IN CAN) TECHNOLOGY M. R. Butler 1, H. Müller 2, and A. Bell 3 1 3 M Health Care Ltd. , Loughborough, Leicestershire, UK, 2 ALTANA Pharma AG, Konstanz, Germany, 3 sanofi-aventis, Crewe, Cheshire, UK Figure 3. Comparison of TLMD for 60 and 120 Actuation Ciclesonide inhalers – 18 pts Bold White Comparison of Ciclesonide 80 mcg TLMD for 60 and 120 Actuation Inhalers In-vitro TLMD Dose Proportionality of Ciclesonide 60 and 120 Actuation Inhalers Image of base of can reaching the internal depth stop 180 100 Mean TLMD (mcg/actuation) Ciclesonide is a corticosteroid, which is converted to an active metabolite (desisobutyryl-ciclesonide) in the lungs. In clinical trials, ciclesonide solution HFA based metered dose inhalers have been shown to be effective in the treatment of persistent asthma in adults (18 years and over), with lung deposition estimated to be approximately 52%. TLMD (mcg / actuation) Introduction Header Figure 2: X-ray Images of Sleeved Canister 90 80 70 140 60 Actuation 120 Actuation Pack Size 60 40 20 0 60 Actuation Pack Size 20 40 60 80 100 120 140 160 Product Strength (mcg/actuation) 180 Figure 4. Comparison of FPD for 60 and 120 Actuation Inhalers In-vitro FPD Dose Proportionality Comparison of Ciclesonide 40 mcg FPD for 60 and n of Ciclesonide 60 and 120 Actuation Inhalers 140. 0 35 120. 0 FPD (mcg/actuation) The consideration of headspace is important since, if not matched, the amount of propellant in the vapour phase would be different leading to slightly differing concentrations of active drug in the formulation (possibly leading to non-comparability in the in-vitro pharmaceutical performance between product pack sizes). The use of the sleeved canister successfully enables the matching of the headspace between the two pack sizes. The output of the exercise to maintain comparable headspace is detailed in Table 1 [2]. Error bars represent 1 SD 80 0 Interference fit of aluminium sleeve onto 5 ml aluminium canister FPD (mcg / actuation) Ciclesonide inhalers are formulated with propellant HFA 134 a and ethanol in three strengths delivering individual doses of 40, 80 and 160 mcg/actuation and are available in two pack sizes delivering a minimum of 60 and 120 actuations. The container and closure for both pack sizes are the same except for the size of the canister used. The 120 -actuation product uses a 10 m. L aluminium canister. For the 60 -actuation product, a ‘sleeved’ (can in can) canister was developed, which incorporates a 5 m. L canister inserted inside an aluminium sleeve (refer to Figures 1 and 2). Therefore, by maintaining the same external dimensions for both product pack sizes, it became feasible to use the same actuator, labelling and packaging, as well as the same automated product manufacturing and packaging processes [1]. R 2 = 1 100 60 Background R 2 = 1 160 30 120 Actuation 60 Actuation R 2 = 0. 9999 100. 0 25 20 R 2 = 1 80. 0 60. 0 Error bars represent 1 SD 40. 0 20. 0 15 0. 0 0 120 Actuation Pack Size 20 40 60 80 100 120 140 160 180 Product Strength (mcg/actuation) 60 Actuation Pack Size Conclusions Figure 1. Schematic Diagram of a 10 ml Canister and a 5 ml Sleeved (Can in Can) Canister 10 ml Canister The investigations have demonstrated that the in-vitro pharmaceutical performance of ciclesonide 60 and 120 actuation inhalers is comparable across the three product strengths. This comparability was obtained for the 60 -actuation product by the use of the sleeved canister, which ensured that the headspace between the two canisters was equivalent. 5 ml Sleeved (Can in can) canister Comparison of Pharmaceutical Performance Represents volume of formulation in canister at first use An in-vitro feasibility exercise was performed to demonstrate whether comparability in pharmaceutical performance between the two pack sizes could be achieved. A key consideration in this exercise was whether the headspace, defined as the percentage of the canister that does not contain formulation in the liquid phase, could be made consistent between the pack sizes. Enabling your success In vitro performance for both the 60 and 120 actutation pack sizes was evaluated to confirm equivalence. Through Life Medication Delivery (TLMD) (Uniformity of Content) and particle size analysis were determined following pharmacopeial guidelines [3, 4 and 5]. Figure 3 compares the TLMD for 80 mcg Ciclesonide p. MDIs for the 120 and 60 actutation packs. Figure 4 compares the Fine Particle Dose (defined as the dose < 5 μm) for 40 mcg Ciclesonide p. MDIs for the 120 and 60 actutation packs. For both the TLMD and FPD, the in-vitro dose proportionality was determined to confirm that the pack sizes remained comparable across the different product strengths. References [1]. J. M. Moore, L. Bradley, P. Charnock and S. Brown (2004), “Container Closure System Solutions for Delivering Low Numbers of Doses from a Pressurised Metered Dose Inhaler”, Respiratory Drug Delivery IX, 333 -336 [2]. M. Butler and H. Müller (2004), “Development of Alvesco® 60 Actuation p. MDIs to Match the Pharmaceutical Performance of the 120 Actuation Product Using Sleeved Can (can in can) Technology”, DDL 15 Proceedings, 61 -64 [3]. ”Uniformity of Delivered Dose”, Preparations for Inhalation, General Dosage Forms, European Pharmacopoeia 4 th edition, 552556, 2002 [4]. “Preparations for Inhalation: Aerodynamic Assessment of Fine Particles”, Methods of Analysis (2. 9. 18), European Pharmacopoeia 4 th Edition, 216 -219, 2002 [5]. “Metered Dose Inhalers and Dry Powder Inhalers”, <601> Aerosols Physical Tests, USP 24, 1896 -1912, 2000 3 Drug Delivery Systems