Modulite : A Simple Solution to a Difficult Problem

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a Vectura Ltd., Chippenham , UK; b Chiesi Farmaceutici SpA, Parma , Italy adoption of the alternative hydrofluoroalkane (HFA) pro- pellants necessitated a shift ...

Formulation and Delivery Respiration 2005;72(suppl 1):3–5 DOI: 10.1159/000083686

Modulite® : A Simple Solution to a Difficult Problem D.A. Lewisa D. Gandertona B.J. Meakina G. Brambillab a

Vectura Ltd., Chippenham, UK; b Chiesi Farmaceutici SpA, Parma, Italy

Key Words Hydrofluoroalkane  Pressurized metered-dose inhaler  Modulite®

Abstract The development of HFA-based pMDIs has proved difficult due to differences in the physico-chemical properties of CFC and HFA propellants. However, the development of solution formulations instead of suspensions has provided a way to formulate products whose cloud characteristics can be modulated in a controlled manner by permuting different formulation and device hardware variables. The new approach has proved successful in formulating several different drugs including steroids and has now been applied to developing a formoterol Modulite® solution formulation characterized by good chemical stability, delivery performance, and clinical results. Copyright © 2005 S. Karger AG, Basel

adoption of the alternative hydrofluoroalkane (HFA) propellants necessitated a shift in design, from suspension formulations to solutions, to accommodate the physicochemical differences between CFCs and HFAs. The greater solubility of many drugs in the new propellants and the development of very potent drugs with therapeutic doses in the order of a few micrograms have made the development of readily dispersable, physically stable suspension formulations difficult. In contrast, solutions have been made possible by the incorporation of ethanol as a low vapor pressure co-solvent within the HFA system, resulting in changes to vehicle polarity and enhancing the solubility of many active substances. Although such solution formulations and the use of ethanol as a co-solvent are not new, interest in solution pMDI technology has grown. This is because high vapor pressure HFA propellants are able to maintain atomization efficiency even when a substantial amount of ethanol is added to the system [2]. Such factors prompted the development of the Modulite® program to reformulate and improve a number of existing products.

Introduction Modulite® Approach ®

Modulite technology is probably best described as a means of manipulating the quality of aerosol clouds generated by pressurized metered-dose inhalers (pMDIs) containing solution formulations; it was specifically designed to address the transition issues surrounding the replacement of chlorofluorocarbon (CFC) propellants instigated by the Montreal Protocol [1]. For some drugs the

© 2005 S. Karger AG, Basel 0025–7931/05/0727–0003$22.00/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/res

The behavior of pMDI formulations is inherently defined by the physical characteristics of the cloud generated on actuation. The size of the particles in the cloud and the speed at which they are expelled from the device determines the quantity of drug reaching the pulmonary target, thus affecting both clinical efficacy and tolerabil-

D.A. Lewis Vectura Ldt. Chippenham, SN14 6FH (UK) Tel. +44 1249 667623, Fax +44 1249 667701 E-Mail [email protected]

7

16

Mean + 25%

4 Mean – 25% 3 2

Delivered dose (µg)

Delivered dose (µg)

5

12 10 8

Mean – 25%

6 4

1

Batch A, Batch B,

Upright Upright

Inverted Inverted

Batch A, Batch B,

2

Upright Upright

Inverted Inverted

0

0 0

a

Mean + 25%

14

6

20

40

60 80 Dose number

100

0

120

b

20

40

60

80

100

120

Dose number

Fig. 1. a Modulite® HFA formoterol 6 g uniformity of delivered dose values through can life after upright and inverted storage. b Modulite® HFA formoterol 12 g uniformity of delivered dose values through can life after

upright and inverted storage.

ity. Modulite® essentially constitutes a new proprietary technology platform that allows the manipulation of inhaled HFA-based solution formulations by the intelligent permutation of a number of variables. These include the quantity of co-solvent, the actuator orifice geometry, the non-volatile components of a solution formula, the volume of the metered solution and the vapor pressure of the propellant [3]. With the Modulite® approach it is possible to develop HFA-based solution formulations where the cloud characteristics are tailored to meet specific needs. This, coupled with a careful selection of the containerclosure system to promote stability, has led to the optimal transition of a number of CFC-based asthma medications, including beclomethasone dipropionate [4] and budesonide [5], to HFA systems.

Formulation of Formoterol Modulite®

The formulation of formoterol fumarate as an HFA pMDI posed a significant challenge; its potency means that an inhalation dosage form providing 6 to 12 g per metered dose achieves the desired therapeutic response. Solubilizing formoterol within an ethanol-based HFA134a system greatly facilitates the reproducibility of batch manufacture and pMDI metering at these low doses. Formulation development resulted in the use of 12% w/w ethanol as co-solvent, initial selection of 50 and 63 l Bespak 357 valves, and the inclusion of 0.024% w/w and

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Respiration 2005;72(suppl 1):3–5

0.038% w/w of 0.1 M aqueous hydrochloric acid as stabilizer for the 6- and 12-g formulations, respectively (Chiesi, data on file). To achieve the desired clinical efficacy, the fine particle (respirable) dose of the HFA solution needed to be adjusted by selecting the diameter of the actuator orifice (as proposed by Meakin et al. [6]). A standard Bespak BK634, 0.30-mm actuator was found to be suitable for both formoterol dose levels.

Drug Delivery Performance and Stability

Drug delivery from suspension formulations can vary according to the ease of redispersion, storage orientation and number of doses fired from the canister. It could be expected that the HFA solution formulation would offer more reproducible dose delivery characteristics [7]. This proved to be the case for formoterol Modulite®. When drug delivery performance was investigated using European Pharmacopoeial procedures [8], formoterol delivery remained uniform throughout the life of the canister. Figure 1 shows delivered dose measured at 20-shot intervals after priming until 120 shots were discharged for both the 6- and 12-g doses, indicating excellent delivered dose uniformity that was well within Pharmacopoeial specifications and Regulatory guidelines; mean delivered dose values are shown in table 1. It is important that dosing remains uniform throughout the life of the device to prevent variable and suboptimal dosing. Aerodynamic as-

Lewis/Ganderton/Meakin/Brambilla

Table 1. Mean drug delivery performance (8 standard deviation) for Modulite® formoterol HFA

Mean RSD n

Formoterol 12 µg

delivered dose, µg

FPD ^4.7 µm, µg

delivered dose, µg

5.180.4 8.1% 28

2.180.2 9.6% 62

10.980.9 3.980.3 8.0% 7.5% 28 146

FPD ^4.7 µm, µg

Can content (mg/n)

2.0

Formoterol 6 µg

1.5

1.0

0.5

FPD = Fine particle dose; RSD = relative standard deviation. 0

sessment of the aerosol cloud generated by the formoterol Modulite® system was also undertaken using the Andersen Cascade Impactor. Results revealed that the fine particle dose (FPD), defined as the mass of drug of a size potentially capable of penetrating to the lower airways during inhalation (approximately below 4.7 m), was 2.1 and 3.9 g for the formoterol 6- and 12-g doses (table 1). FPD values were derived from the stability test data of batches stored either upright or inverted at 5 ° C, 25 ° C/60% relative humidity (see below), or 30 ° C/60% relative humidity. Mean FPD values were also very consistent with relative standard deviations similar to those for delivered dose (table 1). Formulation stability was assessed by storage of pMDIs in both upright and inverted orientations at 5 ° C (refrigerated) and ICH guideline conditions of 25 ° C/60% relative humidity and 40 ° C/75% relative humidity. Residual drug content was determined by total can assay in duplicate. Figure 2 summarizes the mean stability data obtained after 18 months at 5 ° C, 6 months at 25 ° C, and 3 months at 40 ° C. The ‘in-use’ stability was derived by storing pMDIs for 15 months at 5 ° C followed by 3 months at 25 ° C. Data are expressed as can content of

Release

In use

18 months 6 months 3 months 5 C 25 C 40 C

Fig. 2. Stability data for Modulite® formoterol pMDI (12 g).

formoterol. Values for individual cans were all very similar, irrespective of batch or can orientation. The data at 5 and 25 ° C imply that current assigned ‘in-use’ shelf-life (18 months total) could be extended and studies in this area are on-going.

Conclusion

Conventional CFC-containing pMDIs generate coarse, fast-moving clouds which can impede the optimal deposition of drug in the lung. The manipulation of a number of device and formulation variables by the Modulite® technology has redressed these shortcomings and allowed the development of a formoterol HFA pMDI with excellent performance. The drug delivery data above clearly demonstrates there is dose proportionality between the 6- and 12-g formulations of the formoterol HFA pMDI, which is beneficial for prescribers when selecting the optimal product strength for individual patients.

References 1 Montreal Protocol [Accessed 2002, Apr 19] on line. Available from: http://www.unep.org/ ozone/pdf/Montreal-Protocol2000.pdf. 2 Vervaet C, Byron PR: Drug-surfactant-propellant interactions in HFA-formulations. Int J Pharm 1999;186:13–30. 3 Ganderton D, Lewis D, Davies R, Meakin B, Brambilla G, Church T: Modulite: A means of designing the aerosols generated by pressurized metered dose inhalers. Respir Med 2002; 96:S3–S8.

Modulite®: A Simple Solution

4 Bousquet J, Cantini L: Clinical studies in asthmatics with a new non-extra fine HFA formulation of beclometasone dipropionate (BDP Modulite). Respir Med 2002;96:S17–S27. 5 Vastagh E, Kuna P, Calistruc P, Bogdan MA: Efficacy and safety of inhaled budesonide delivered once or twice daily via HFA-134a in mild to moderate persistent asthma in adult patients. Comparison with budesonide CFC. Respir Med 2003;97:S20–S28.

6 Meakin BJ, Lewis DA, Ganderton D, Brambilla G: Countering challenges posed by mimicry of CFC performance using HFA systems; in Dalby RN, Byron PR, Farr SJ, Peart J (eds): Respiratory Drug Delivery VII. Raleigh, NC, Serentec Press, 2000, pp 99–108. 7 McDonald KJ, Martin GP: Transition to CFCfree metered dose inhalers – into the new millennium. Int J Pharm 2000;201:89–107. 8 European Pharmacopoeia. 2002 4th Ed, European Directorate for the Quality of Medicines, Strasbourg, France.

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