Comparison of Pharmaceutical Performance DEVELOPMENT OF CICLESONIDE 60 ACTUATION HFA pMDIs 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 3M Health Care Ltd., Loughborough, Leicestershire, UK, 2 ALTANA Pharma AG, Konstanz, Germany,3 sanofi-aventis, Crewe, Cheshire, UK Header Figure 2: X-ray Images of Sleeved Canister – 18pts Bold White Introduction Figure 3. Compari son of TLMD for 60 and 120 Actuation Ciclesonide inhalers Comparison of Ciclesonide 80mcg TLMD for 60 In - vitro TLMD Dose Proportionality of and 120 Actuation Inhalers Ciclesonide 60 and 120 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%. Inhalers Image of base of can reaching the internal depth stop T L M D ( m c g / a t u i o n ) 6 A P k S z e 1 2 9 8 7 R 2 = 1 20 40 60 80 100 120 140 160 180 Product Strength (mcg/actuation) Mean TLMD (mcg/actuation) 60 Actuation 120 Actuation Error bars represent 1SD Error bars represent 1SD Background Interference fit of aluminium sleeve onto 5ml aluminium canister Ciclesonide inhalers are formulated with propellant HFA 134a 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 10mL aluminium canister. For the 60-actuation product, a ‘sleeved’ (can in can) canister was developed, which incorporates a 5mL 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]. Figure 4. Comparison of FPD for 60 and 120 Actuation Inhalers Comparison n of Ciclesonide 40mcg FPD for 60 and In - vitro FPD Dose Proportionality of Ciclesonide 60 and 120 120 Actuation Inhalers Actuation Inhalers 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]. F P D ( m c g / a t u i o n ) 6 A k S z e 1 2 3 5 R 2 = 1 = 0.9999 0.0 20.0 40.0 60.0 80.0 100.0 120.0 140.0 20 40 60 80 100 120 140 160 180 Product Strength (mcg/actuation) FPD (mcg/actuation) 120 Actuation 60 Actuation Error bars represent 1SD Conclusions Figure 1. Schematic Diagram of a 10ml Canister and a 5ml Sleeved (Can in Can) 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. 5ml Sleeved (Can in can) canister 10ml Canister Comparison of Pharmaceutical Performance References 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 pMDIs for the 120 and 60 actutation packs. Figure 4 compares the Fine Particle Dose (defined as the dose < 5 μm) for 40 mcg Ciclesonide pMDIs 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. [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 pMDIs 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 4th edition, 552-556, 2002 [4]. “Preparations for Inhalation: Aerodynamic Assessment of Fine Particles”, Methods of Analysis (2.9.18), European Pharmacopoeia 4th Edition, 216-219, 2002 [5]. “Metered Dose Inhalers and Dry Powder Inhalers”, <601> Aerosols Physical Tests, USP 24, 1896-1912, 2000 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. 3 Drug Delivery Systems Enabling your success