Formulation of pMDI Systems

Advances in Suspension-Based pMDI Systems

Due to the poor solvent properties of HFAs, suspension based systems are a popular formulation route for current pMDIs. In general, research in this area has focused on two main themes over the past 5 years: particle engineering and the application physical stabilizers.

As with DPI systems, the drug particles used in suspension based systems should ideally have a diameter of less than 6 ^m to achieve a therapeutic affect upon administration. As previously discussed, these particulate systems have a high surface area to mass ratio and therefore tend to be highly cohesive/adhesive in nature. Although, effects such as humidity plays a minor role in pMDI systems, the presence of solvation, van-der Waals, and electrical double layer forces, as well as density effects, may result in suspension instability and uncontrolled agglomeration and/or caking. Until recently, suspension pMDIs were mostly comprised of micronized drug particles. As previously discussed, micronization is a high energy process that leads to a broad particle size distribution and allows poor control over particle morphology and density. Although this approach is still used in current pMDI suspensions, research has focused on improving internal stability by particle engineering, especially in light of increasingly stringent regulatory standards proposed for pMDIs. Since many examples of particle engineering technologies exist only a limited few that are specifically related to pMDI suspension technology are discussed here.

Media milling is a concept that has found some application in biopharmaceutical processing and may be applicable to pMDI suspensions. Media milling incorporates the suspending medium (i.e. HFA) into the processing step, such that the final production step is conducted in situ and the final product can be extracted at the mill output. The adaptation of this technique to in situ pressurized milling has had some success. For example, work conducted by Lizio et al. (92) suggested that this methodology could be successfully used to produce a pMDI suspended peptide formulation containing particles with a volumetric mean diameter of 3.1 ^m, without generating degradation products or contaminants from the milling process. Similarly, DuPont workers, reported increased formulation stability of in situ media milled budesonide formulations when compared to conventionally micronized particulate suspensions (93).

Another approach for improving stability via modified particulate milling is to process the drug with pharmaceutical stabilizers by co-grinding. For example, Williams et al. (94) investigated the effect of co-grinding a model drug, triamcinolone acetonide (TAA), with a polymeric surfactant (Pluronic F77). The co-processed material exhibited reduced propellant solubility, increased formulation stability and improved aerosol dispersion (resulting in increased FPF) when compared to a TAA control.

Apart from co-processing methodologies, specific particle engineering techniques may be employed to improve suspension stability. In general, any of the particle engineering methodologies discussed in the DPI section of this chapter may be utilized. However, of note is the use of porous particles (15,81). As with DPI formulations, the control of the density, particle size distribution, and porosity of the powder can affect the relative surface area to mass ratio thus modifying the adhesion characteristics. However, in addition, for pMDI systems the rate of sedimentation (or creaming), will be directly related to the densities of the media and the particulates. Thus, by modifying the density of the API powder it may become possible to "density match" the formulation and thus create a stable system. This approach was employed in Nektar's PulmoSphere technology (81). Furthermore, by incorporating a porous surface topography and spherical morphology, contact area effects are minimized.

The monitoring of particle surface energy is another possibility that has been explored in order to improve the suspension stability in pMDIs. For example, the atomic force microscope colloidal probe technique (as described previously) may be used to measure the forces between individual micron sized particulates in model propellants, similar to those used in pMDIs, namely, pressurized HFAs (95,96). Furthermore, these techniques can be expanded to investigate the relationship between drug-drug interactions, surface free energy, and in vitro performance (97,98).

An alternative option to particle engineering is the use of HFA soluble surfactants and/or stabilizing agents. The molecules in these materials reduce particulate interactions by accumulating at the interface of the colloidal particles and act to either reduce interfacial tension, produce steric hindrance between particulates, or form colloid bridges to increase flocculation. An example of the influence of polymeric additives, such as polyethelene glycol (PEG) on drug cohesive forces is represented in Figure 14. As can be seen from Figure 14, particle cohesion in this model system is dependent on both the concentration and the molecular weight of the polymer used (99).

It is not surprising that there has been a significant focus on HFA stabilizing agents for pMDI applications since they may provide a more immediate, and less costly, alternative to particle engineering. Indeed, historically, CFC formulations were stabilized using surfactants such as oleic acid. Unfortunately, these molecules were incompatible with the replacement HFAs and alternatives have been sought. Such excipients include long chain polymers, such as PEG (100) and polyvinylpirrolidone (101); fluorinated carboxylic acids or ester surfactants (102) and hydrophilic surfactants (103). Furthermore, the solubility of conventional CFC pMDI surfactants (e.g. oleic acid, lecithin) may be utilized by using specific co-solvents (104).

Oleic Acid Hydrophilic

Figure 14 Influence of PEG molecular weight and concentration on drug-drug interactions in a model pMDI system. Abbreviations: PEG, polyethelene glycol; pMDI, pressurized metered dose inhaler.

Figure 14 Influence of PEG molecular weight and concentration on drug-drug interactions in a model pMDI system. Abbreviations: PEG, polyethelene glycol; pMDI, pressurized metered dose inhaler.

Solution-Based pMDI Systems

The most obvious approach for overcoming suspension stability issues in pMDIs is to solubilize the drug in the propellant, with or without co-solvents. This approach has obvious advantages. Since the drug is effectively present as a molecular dispersion any issues with flocculation, sedimentation, Oswald ripening, particle-device/component adhesion, and metering consistency are overcome. However, it is important to note, new challenges are faced with solution pMDI systems. For example, in most cases, the drug will not be directly soluble in the non-aqueous propellant and will require a considerable amount co-solvent for solublization. Furthermore, the formulation may be chemically less stable (and require stabilizers to reduce degradation) or may be more prone to temperature cycle instabilities and precipitation.

Apart from the improvement in physical stability and metering consistency, a key advantage of using solution pMDI technology is the potential to accurately control the particle size distribution of the resulting aerosol. For suspension based systems, the aerosol particle size will ultimately be governed by the drug particulate size and adhesive/cohesive interactions. In comparison, the spray pattern and final aerosol particle size distribution of a solution based system will be governed by the vapor pressure of the propellant, the proportion and volatility of co-solvent and the dimensions of the actuator orifice. By controlling these parameters in a system containing volatile co-solvents, the final particle size distribution will depend on the drug concentration in the aerosol droplets.

The most successful example of pMDI solution based systems is 3Ms beclomethosone dipropionate formulation; Qvar® (105) which utilizes ethanol as a co-solvent. As discussed above, in comparison to suspension based pMDIs, the FPF of the aerosol cloud is not be dependent on micronized API size (and interactions) but on the size of the evaporating propellant/co-solvent droplets. Subsequently, the aerosol mass median aerodynamic diameter of Qvar beclometasone is reported as 1.1 ^m (less than most conventional suspension pMDI formulations), resulting in improved respiratory deposition (between 50% and 60% as measured in human studies) (106).

As with the Qvar system, the use of volatile co-solvents in pMDI solution formulations may yield particles with small aerodynamic diameters (of the order 0.8-l.2 ^m). Although this size range is clearly suitable for respiratory delivery, it will generally result in a product targeted largely to the alveoli, which for generic API formulations, may not be comparable to existing deposition patterns and clinical efficacy.

One method of controlling the aerosol particle size of solution based pMDI formulations is by addition of a non-volatile component into the formulation (107,108). The presence of a non-volatile additive in a soluiblized HFA-volatile-co-solvent system will result in an increase in the final droplet size. Since evaporation is dependent on the initial solution composition, the integration of a non-volatile component, such as glycerol, into the primary pMDI solution will result in the final aerosol containing both drug and non-volatile additive. Subsequently, after evaporation of the volatile components the resultant particulate size will be dependent on the concentration of the non-volatile component which will dominate the particle size. This approach has been successfully employed in the Modulite® technology developed by Chiesi, which, depending on the nonvolatile concentration of glycerol or polyethylene glycol, has resulted in the ability to modify the aerodynamic diameter of the resultant aerosol (Fig. 15) (107).

In addition to simple co-solvents, and the addition of non-volatile agents which modify aerosol particle size, significant advances have been made using alternative solubilizing agents. For example, hydrophilic and hydrophobic excipients that are HFA-soluble have been recently developed. Examples of these novel excipients include oligolactic acids (OLAs). These acids, first introduced as suspension aids, are short-chain polylactides that, in the absence of co-solvents, degrade to endogenous lactic acid. The OLAs, with an average of 6-15 repeat units, interact with the API to form API/ excipient complexes that are highly soluble in HFA propellants (>5% w/w). These OLAs have no detectable toxicity, as measured by radio-labelled

Advances in Pulmonary Therapy 29 5 -

Advances in Pulmonary Therapy 29 5 -

Pmdi Components

0 1 2 3 4 5 6 7 Total non-volatile component (%w/w)

0 1 2 3 4 5 6 7 Total non-volatile component (%w/w)

Figure 15 Effect of total content of non-volatile component on MMAD of BDP pMDI solution formulations in HFA 134a. Abbreviations: MMAO, mass median aerodynamic diameter; BDP, beneficiary database prototype; pMDI, pressurized metered dose inhaler. Source: From Ref. 108.

distribution, and inhalation safety studies (109). A further advantage of this new excipient class is the potential for OLA-drug matrix formation to provide the potential for sustained drug release in a very simple, economical manner, potentially increasing the efficacy of many compounds (Fig. 16).

One drawback of OLA excipients is that they are water insoluble, making the pre-formulation and solubilization of polar drugs difficult. Consequently, another group of hydrophilic excipients based on functional-ized PEGs are available for use with biopharmaceuticals or small molecules in HFA pMDIs (111). These compounds, generally used at low concentrations relative to the drug, are also readily soluble in both HFA 134a and 227 (alone, or with minimal amounts of ethanol). Furthermore, these functionalized PEGs also have the potential to form ion-pairs with drug salts. For example, 3M workers examined the ability to prepare HFA-soluble ion-pairs and reported significant improvements in solubility in HFA/ethanol systems (111). Other solubility improving compounds include mono-amides and mono-esters, two ubiquitous substances in the body that degrade to endogenous or known biocompatible compounds. These new mono-functionalized excipient-drug complexes, when combined with ethanol solvents, have recently been reported to increase solubility of a drug to 1.5 wt%, which corresponds to an ex-valve dose of over a milligram (111).

In addition to solution based systems, other "molecular dispersions" may be formed using reverse micelles and microemulsion technology. These systems have the same advantages in terms of aerosol performance, as pure

Modified Release Medication
Figure 16 Sustained release of Butixicot (steroid) using OLA as a sustained-release matrix following pMDI aerosolization. Abbreviation: OLA, oligolactic acids. Source: From Ref. 110.

solution based systems, but may have the potential for incorporation of molecules that will not be soluble using conventional co-solvents. Although these formulation strategies are not currently utilized in pMDI products, a limited number of studies have investigated these systems in HFA propellants. For example, Butz et al. (112) reported that water soluble compounds could be emulsified in a water-in-fluorocarbon emulsions (using a perfluorooctyl bromide dispersed phase and perfluoroalkylate-dimorpho-linophosphate stabilizing surfactant). The subsequent emulsion was readily dispersible in all proportions in both HFA 134a and 227 (112). Other molecular dispersants include cyclodextrins. Cyclodextrins have been used extensively to form inclusion complexes with many substances since the complex exhibits higher aqueous solubility and improved chemical stability. This approach can be utilized in pMDI systems, as reported by Williams and Liu (113), who investigated a novel technique of incorporating aspirin in a hydroxypropyl-P-cyclodextrin inclusion complex in HFA 134a.

Advances in pMDI Device Design

Apart from the pMDI formulation approaches discussed above, product efficiency, patient compliance, and usability will also be governed by the functionality of the device itself. In simple terms, pMDI devices contain 5 key components, namely, the pressurized canister, the actuator device/

canister housing, the valve components, crimp seal components, and actuator (Fig. 17).

Dose counting: In comparison to multi-dose DPI systems, which integrated dose counting mechanisms into the earliest devices, pMDIs have, until recently, had no convenient way for patients to track the number of doses remaining in the canister at any given time. Indeed, in early pMDI systems, patients could keep track of pMDI usage by recording each dose taken manually on a record sheet, and subtracting the total from the labeled number of doses. Alternatively, patients could test the fill volume by a rudimentary float-test.

Such unreliable methods often lead to patients throwing away a product which still contained an acceptable number of doses or using a product beyond the recommended number of doses, the latter being potentially dangerous as patients could be inhaling sub-therapeutic doses. A recent survey of 342 adult asthmatics conducted in 2004 by Dr. Bradley E. Chipps, of Capital Allergy and Respiratory Disease Centre in Sacramento (California), reported that 62% of patients had no idea that they were supposed to keep track of the dose status of their pMDI (114). Amongst those who knew, only 24% were aware of what was left in their pMDI, 25% of subjects found their MDI empty when they needed it, and 8% of those people ended up calling 911 emergency for help (114).

In 2003, the FDA issued guidance for the industry concerning the incorporation of dose counting technologies in pMDI devices. This announcement prompted the industry to accelerate development of several dose-counter technologies, resulting in a surge in activity and the filing of

Trudell Dose Counter
Figure 17 Schematic representation of a conventional pMDI.

more than 30 patents relating to counting systems by several drug delivery device companies. These included Bespak, KOS, Trudell Medical, and Valois Pharmaceutical Divisions. These companies offered proprietary technologies such as the requiring 50% less force to release a dose. This is especially important for the elderly and young children. Commercially, in 2004, GlaxoSmithKline led the way in applying these new FDA dose counting guidelines by launching the Seretide® Evohaler® in the United Kingdom.

Overcoming patient coordination/improving the patient experience: Many patients find it difficult to coordinate the actuation of their pMDI with inhalation maneuvers. Overcoming this potential hurdle was one of the key attractive features that have been promoted as an advantage for passive DPI systems. Furthermore, inspiratory flow rate can influence the dose emitted from an inhaler, the amount inhaled, the oropharyngeal deposition, and the regional lung deposition of inhaled medications (115). Consequently, the effective use of conventional pMDIs, as shown in Figure 17, is technique dependent (116,117).

In the late 1960s, development began on the first breath-actuated inhaler. Having seen the difficulty that some patients experienced when coordinating pressing and breathing, an opportunity was identified for a device that would actuate as the patient breathed in. This would eliminate the need for coordinated actuation or the use of add-on devices such as aerosol-holding chambers.

The first Autohaler® device was launched as the Duohaler® in 1970. The Autohaler was pocket-sized and easy for patients to use, however some complained that the loud "click" that sounded when the mechanism fired was disconcerting. The device did not gain instant popularity and was shelved until work began on an improved device in the 1980s. Subsequently, pirbuterol (Maxair, 3M, St Paul, Minnesota) and albuterol HPA (IVAX Laboratories, Miami, Florida) are now available in the Autohaler. Similar breath actuated pMDI device designs include the Baker Norton Easyhaler®, the more recent Xcelovent® (Meridica/SkyePharma) and CCLs Integrated Breath Actuated Inhaler with dose counter. In general, these devices have a mechanical flow trigger that, after priming, actuates the release of the drug when the patient's inhalation airflow reaches a required flow rate (e.g. 301/ min). As expected, this approach has been shown to improve drug delivery in adults and children with poor coordination (118-120).

Just as coordination influences patient compliance, so does the aerosol plume velocity and temperature. Since pMDI formulations are based on the volatile evaporation of a unit dose, the resultant aerosol may travel at high velocity and be "cold". This relationship can be visualized when comparing the plume velocities of commercially available pMDIs, where plume forces have been reported as varying between 29 and 117 mN and temperatures between —32°C and +8°C (when measured 5 cm from the end of a actuator mouthpiece) (121). These patient "feel" issues may result in a reluctance and/or difficulty for effective patient inhalation, since the Freon effect, in combination with particle impaction, is felt at the back of the throat; possibly causing a gagging effect.

Developments in the design of actuators, notably the use of actuators with smaller orifice diameters which produce a much slower, "warmer" spray, may improve patient co-ordination and compliance. By using actuators with small orifice diameters, it is possible to produce a relatively slow and "warm" spray from HFA pMDIs, compared with traditional CFC products (122). This approach makes it easier for a patient to coordinate the act of firing the pMDI with an inhalation maneuver. Furthermore, for solution based systems, if the unit dose remains constant, and the orifice diameter is reduced, the reduction in actuator orifice diameter will result in increased FPF (123) (Fig. 18). For solution based systems, the relationships between, for example, co-solvent, non-volatile component and actuator orifice were developed by Lewis et al. (107,108,124) into a set of empirical equations that could describe the performance of a pMDI based on formulation variables.

Improvements to internal pMDI components to increase therapeutic outcomes: Other advances in pMDI device technology have been a result of the modification of canister components, including valve, crimp assembly and internal canister materials.

For example, conventional metering valves are designed in such a way, that a metered volume of liquid is retained, by surface tension, in the chamber after an actuation. The nature of such valve designs results in priming issues, and where suspensions are used, homogeneity issues. To overcome this, valves are being developed with either more "open valves" or

■ Bespak BK830 series


o Laser-drilled inserís LD 1 - 5


---Besi III lor all dala




Actuator orifice diameter (mm)

Actuator orifice diameter (mm)

S 50

■ Bespak BK630 series -i Laser-drilled Inserts LO i o Laser-drilled Inserts LD 2 ■ 5 ---Best til lor diameter >0.14rmm

Actuator orifice diameter (mm)

Figure 18 Relationship between actuator orifice diameter and (A) plume and (B) FPF for a solution-based pMDI. Source: From Ref. 125.

virtual metering tanks, which only form a closed system on actuation. These improvements increase dose reproducibility, remove priming effects, and potentially increase therapeutic outcomes (126). Furthermore, these developments in valve technology, particularly the "Easi-fill" valve (BK361 Bespack, Fig. 19), can be incorporated into new pMDI designs with relative ease.

Since pMDI formulations are pressurized systems, the crimp assembly and internal seals are important components since they should, for obvious reasons, avoid propellant leakage, and moisture ingress. As with the formulation issues that arose with the conversion of CFCs to HFAs, the simple switch using conventional canister components was not straight forward, since the solvent properties of HFA propellants (and co-solvents) affected the degree of elastomer swelling (or shrinkage) and increased propellant leakage when compared to the CFC based formulations (127). In order to overcome such issues, alternative elastomer materials with improved HFA compatibility were required. The Spraymiser™ Valve (3M) (128) is a new generation of valve that incorporates a number of EPDM (Ethylene Propylene Diene) elastomers that can offer additional benefits to the performances of HFA pMDI products, that is, improved sealing, elimination of valve sticking, etc. Furthermore, the new materials contained reduced levels of extractable materials (129). This was to become increasingly important since the FDA endorses for more stringent guidance for levels of acceptable extractables (130). For a pMDI, the PQRI (Product Quality Research Institute, Virginia, USA) leachable and extractable working group recommends: "that AETs (Analytical Evaluation Threshold) for MDI leachables profiles be based on the Safety Concern Threshold of 0.15 mg/day for an individual organic leachable. This recommendation includes potential organic leachables derived from critical

Core Base

Core Base

Bespak Valves

Figure 19 Bespak BK361 "Easi-fill" valve, schematic cross-sectional drawing. The larger flow path in comparison with a standard metering valve enables an easier fill and drain. Source:

Figure 19 Bespak BK361 "Easi-fill" valve, schematic cross-sectional drawing. The larger flow path in comparison with a standard metering valve enables an easier fill and drain. Source:

components of the dose metering valve, canister inner surface, and inner surface coating if present." Subsequently, there are numerous patents that include the uses of novel materials or describe new methods for the removal of sources of polynuclear aromatic compounds, but this aspect of the pMDI valve development is beyond the scope of this chapter.

As previously discussed, the surface area to mass ratio of suspended particles used in pMDI inhalation formulations results in a high adhesion potential. Consequently, exposed material surfaces inside the pressurized canister may facilitate adhesion and thus reduce emitted doses throughout the lifespan of a device. Although this may not be critical for conventional dose pMDIs, where small variations in drug loss may not influence the required pharmacopoeial tolerances, it may be critical for lower dose or more adhesive APIs. An example of the relative differences in the median adhesion forces between single micronized albuterol sulphate particles and three materials used in pMDI canisters is shown in Figure 20, which shows that there is a difference of two orders of magnitude in the drug adhesion to the components. In view of these potential issues, a series of coatings have been developed, namely fluorinated polymers (131), which are now utilized in the Ventolin® HFA product (132). These coatings are generally made of relatively inert organic materials, such as perfluoroalkoxyalkane, epoxy-phenol resin, and fluorinated-ethylene-propylene polyether sulfone (133),

Figure 20 Median adhesion between an albuterol particle and three surfaces used in pMDI canister construction collected in a model HFA propellant using colloid probe microscopy. Source: From Ref. 95.

Components Pmdi

Figure 20 Median adhesion between an albuterol particle and three surfaces used in pMDI canister construction collected in a model HFA propellant using colloid probe microscopy. Source: From Ref. 95.

which have low surface energies and are thus are less likely to cause particle adhesion (134) (Fig. 21).

The major developments in pMDI formulation and technology have been reviewed and an overview provided as to how the latest advances in aerosol technology have been used in order to improve upon existing inhaler performance. There are a multitude of formulation and device factors to consider when developing a pMDI. For these reasons a multiplicity of approaches have been applied for the determination of the effect of such variables on performances. As a result, although much is known about pMDIs at the empirical level, a systematic approach between in vitro measurements and in vivo clinical outcomes has been clearly missing.

Continue reading here: Recent Advances in Nebulizer Technology

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  • Maddalena
    What are excipient IN PMDI?
    2 years ago
  • maxwell
    9 years ago