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(BQ) Part 2 book “Pulmonary drug delivery” has contents: Particle engineering for improved pulmonary drug delivery through dry powder inhalers, particle surface roughness – its characterisation and impact on dry powder inhaler performance, drug delivery strategies for pulmonary administration of antibiotics,… and other contents.
8 Particle Engineering for Improved Pulmonary Drug Delivery Through Dry Powder Inhalers Waseem Kaialy1,∗ and Ali Nokhodchi2,3,† School of Pharmacy, Faculty of Science and Engineering, University of Wolverhampton, UK School of Life Sciences, University of Sussex, UK Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Iran Abbreviations List of Abbreviations 𝛼 𝜌true or Dtrue API AFM CI CCM d50% Dae Db Dg or De Dt DPI EM ED ER Angle of repose True density Active pharmaceutical ingredient Atomic force microscope Carr’s index Cooling crystallised mannitol Median diameter Aerodynamic diameter Bulk density Geometric diameter Tap density Dry powder inhaler Emission Emitted dose Elongation ratio ∗ w.kaialy@wlv.ac.uk † a.nokhodchi@sussex.ac.uk Pulmonary Drug Delivery: Advances and Challenges, First Edition Edited by Ali Nokhodchi and Gary P Martin © 2015 John Wiley & Sons, Ltd Published 2015 by John Wiley & Sons, Ltd 172 Pulmonary Drug Delivery FPD FPF GAS GSD HR IGC IL LPPs MMAD PGSS pMDI PSD PSG RD RESS SCF SEDS 8.1 Fine particle dose Fine particle fraction Gas antisolvent Geometric standard deviation Hausner ratio Inverse gas chromatography Impaction loss Large porous particles Mass median aerodynamic diameter Precipitation from gas saturated solutions Pressurised metered dose inhalers Particle size distribution Pressure swing granulation Recovered dose Rapid expansion of supercritical fluid solution Supercritical fluid Solution enhanced dispersion by SCF Introduction Oral drug delivery is the most commonly used delivery route for many drugs due to its several advantages, which include ease of administration and high patient acceptability Nevertheless this route of drug delivery does have a number of associated disadvantages such as possible unpredictable absorption rates [1], the potential for drug degradation by the digestive acid and enzymes, as well as drug inactivation in the liver and the lack of organ selectivity (compared to that achievable by other routes including the pulmonary) Drug delivery by inhalation has been employed routinely for the treatment of localized diseases such as asthma and other pulmonary conditions Delivery via the airways has also been used in the treatment or management of systemic diseases (e.g., diabetes) [2, 3] Recombinant human deoxyribonuclease (rhDNase, dornase alpha) was the first recombinant protein approved for therapeutic use by inhalation delivery [4] It is apparent, therefore, that this route of drug delivery is important, but performance of inhalation products is still generally poor This is one of the main reasons for interest in the modification of drug or carrier particles by particle engineering, so as to enhance the performance of formulations in vivo, and as assessed in vitro 8.2 Dry Powder Inhalers Dry powder inhalers (DPIs) comprise a pharmaceutical dosage form of increasing popularity with attractive features such as the provision of a propellant-free means of drug delivery and such formulations have rapidly increased in number, worldwide Some of the most commonly used DPI dosage forms are shown in Figure 8.1 More discussion and details on specific inhaler devices are available elsewhere (see Chapter 3) 8.3 Particle Engineering to Improve the Performance of DPIs In attempts to enhance the efficiency of delivery from DPIs, several techniques have been utilised to prepare particles of active pharmaceutical ingredients (APIs) and carriers (e.g., lactose or mannitol), Particle Engineering for Improved Pulmonary Drug Delivery EasyhalerTM TurbulaherTM DiskhalerTM AerolizerTM ClickhalerTM RotahalerTM HandihalerTM 173 SpinhalerTM TwisthalerTM NovolizerTM Figure 8.1 Some common DPI devices under controlled conditions These include simple crystallization techniques, spray-drying, freezedrying, supercritical fluid (SCF) technology and antisolvent technology These are considered in turn 8.3.1 Crystallization A crystallization process is characterized by the formation of supersaturation, nucleation and crystal growth, in addition to secondary phenomena including aggregation, agglomeration, breakage, re-dissolution and aging [5] Crystallization is usually associated with several challenges including poor mixing and crystal break/agglomerate formation [6] Fundamentally, the difference of the chemical potential between the supersaturated solution and the solid crystal face is the driving force for crystallization Typically, supersaturation can be created in the crystallization media by cooling, evaporation of the solvent and/or the addition of an antisolvent Batch cooling crystallization is a widely used technique for the production of high-value chemicals [7] The slow crystallization rate is the main disadvantage of the cooling crystallization technique [8] This is due to the relatively large width of the metastable zone that requires a high supersaturation to induce crystallization [9] Nevertheless, slow cooling is advantageous in terms of attaining the maximum yield, minimum agglomeration [10], fewer defects in the crystal lattice [11] and high product purity [12] Antisolvent crystallization is a process where an organic product can be recovered from aqueous solutions through the addition of non-solvent compounds by which the solute solubility is decreased, without creating a new liquid phase [13] The successful antisolvent must be miscible with the mother liquid but in which the solute is insoluble Under such conditions, solute solubility is reduced but not completely inhibited Antisolvent crystallization using alcohols does suffer from disadvantages including the requirement for solvent recovery and the risk associated with the use of flammable solvents at high reaction temperatures [14] Crisp et al [15] reported that the crystal size increased as the antisolvent proportion decreased The antisolvent crystallization technique has been proven to be a potential technique for the preparation of particles, such as salbutamol sulphate [16] and budesonide [17], both generated an improved DPI performance upon aerosolization (Figure 8.2) It has been documented that the properties of an antisolvent crystallized product are dependent on several processing parameters such as the type of the antisolvent [18], solution concentration [19], agitation intensity [20], antisolvent addition rate [21] and mixing conditions [22] During 174 Pulmonary Drug Delivery (a) Salbutamol sulphate (b) Budesonide Figure 8.2 Engineered drug particles prepared by antisolvent crystallization for DPI systems: (a) salbutamol sulphate (Source: Reproduced from [16], with permission from Elsevier) and (b) budesonide (Source: Reproduced with permission from [17] Copyright © 2008, American Chemical Society) crystallization, mechanical stirring can introduce random energy fluctuations within the solution leading to a heterogeneous distribution of local concentrations, resulting in heterogeneous crystal growth [23] On the other hand, particles with a narrow size distribution and a regular particle shape can be prepared by suspending the crystals in a gel [24], in which secondary nucleation (heterogeneous nucleation) occurs to a much lesser extent [25] 8.3.2 Spray-drying Spray-drying is a drying technique in which a dry powder is produced by evaporating the liquid from the atomized feed when it mixes with the drying hot gas medium In DPIs, the spray-drying technique has been employed to produce not only drug particles [26–29] but also carrier particles [26, 30, 31] A few examples are shown in Figure 8.3 Spray-dried drug particles can produce higher respirable fractions than micronized particles, and this has been ascribed to their spherical shape resulting in less drug–carrier contact area and in turn less drug–carrier adhesive forces [23] (Figure 8.4) Moreover, spray-dried particles may have more homogenous particle size distribution (PSD) [33] One of the most important advantages of spray-drying techniques is the opportunity to generate particles with pre-determined characteristics, e.g., size, morphology, shape and density, seeking to optimize the powder properties such as bulk density, flowability and dispersibility [34] Such characteristics of the spray-dried particles can be controlled by manipulating several parameters including the composition of the solvent [35] and coating of particles by an excipient (e.g., leucine) In addition, other parameters such as solute concentration, solution feed rate, gas feed rate, drying rate, viscosity of the liquid feed and relative humidity are able to alter the characteristics of the resultant spray-dried particles [36] Various methods can be employed to determine aerosol PSDs, which depend on various geometric features or physicochemical properties of powders being measured Among these, Dae is the most used and most relevant parameter to express aerosol particle size [37], a parameter that also accommodates particle shape Furthermore, the Dae relates to the main mechanisms of particle deposition and is defined as the diameter of a sphere having the same volume and a unit density This assumes that such a ‘hypothetical’ particle impacts on the same stage of the impactor during aerosolization (or has the same impaction characteristics) as the real particles being measured [38] The theoretical Dae of particles (Dae = Dg × (𝜌true /X)0.5 ) can be calculated from the particle true density (𝜌true or Dtrue ) and geometric diameter (Dg ) [39] Particle Engineering for Improved Pulmonary Drug Delivery (a) Gentamicin (c) Budesonide μm (b) 175 μm Cromolyn μm (d) Mannitol 200 μm Figure 8.3 SEM photographs for different particles used in DPI systems: (a) gentamicin (Source: Reproduced from [27], with permission from Elsevier), (b) cromolyn (Source: Reproduced with permission from [28] Copyright © 2007 Wiley-Liss, Inc.), (c) budesonide (Source: Reproduced from [29] with kind permission from Springer Science and Business Media) and excipient: (d) mannitol (Source: Reproduced from [31], with permission from Elsevier) Micronized drug High drug-carrier contact area Carrier surface Spray-dried drug Less drug-carrier contact area Carrier Carrier surface surface Figure 8.4 Schematic representation of drug–carrier interactions of a micronized drug and a spray-dried drug (SEM images taken from Louey et al (Source: Reproduced from [32] with kind permission from Springer Science and Business Media) 176 Pulmonary Drug Delivery Table 8.1 Comparison between drug carrier, Pulmosphere® and large porous particle DPI formulations Formulation type cm –3 ) Density (g Mean geometric diameter (μm) Drug-carrier Pulmospheres® Large porous particles ± 0.5 10 As seen, Dae can be changed by changing three factors: particle size, particle density and particle shape factor (X) For example, to decrease the Dae particle size and particle density can be decreased and dynamic shape factor can be increased By definition, the particle in which the Dae is equal to the physical diameter is a water droplet with a density of g cm –3 A drug particle that has a particle density more than g cm –3 will have Dae higher than its Dg In practice, Dae is usually measured by the techniques that are dependent on inertial impaction Indeed, aerosol PSD can be expressed in two ways: based on the number of particles (count median Dae ) or mass (mass Dae ) An advantage of the spray-drying technique is the capability to produce large porous particles (LPPs) LPPs are particles with mass density significantly less than g cm –3 , such that a low (respirable) aerodynamic diameter (Dae ) can be achieved but with the particles having a mean geometric diameter (Dg or De ) greater than 10 μm [40], or even as high as 20 μm [41] (Table 8.1) LPPs can be prepared by a standard, one-step pharmaceutical spray-drying process using ‘generally recognized as safe’ (GRAS) excipients [42] The advantages of LPPs are summarized as follows: a Increased aerosolization efficiency due to lower powder aggregation owing to a lower contact area between larger particles resulting, in less total van der Waals forces Several studies have shown that LPPs increase the amount of respirable particles, both in vitro [43, 44] and in vivo [3, 45] b Formulations containing LPPs may confer a longer time for drug delivery to occur, because they can escape the natural clearance mechanisms present in the airways such as the mucociliary escalator (Chapter 1) and phagocytosis by alveolar macrophages [41] c Formulations containing LPPs of APIs with relatively low water solubility (i.e., relatively lipophilic LPPs) have been produced so as to generate sustained release from inhaled products [42] Despite these advantages, some disadvantages have been stated in connection with LPP formulations For example, LPP formulations can impose a limit on the deliverable dose because they can carry only a small mass of drug due to the low density (by definition) of such particles, so they provide only a practical means of delivery for potent and low-dose drugs [46] Generally, there are only two basic strategies by which aerosol particles can be made In strategy 1, aerosol particles are produced with approximately a unit density (g cm –3 ), with the respirable particle size requiring a geometric size between and μm In strategy 2, the density of particles can range between 0.04 and 0.6 g cm –3 , but the mean Dg of the particles should be between and 15 μm Biodegradable microspheres have been produced with a sponge-like appearance, having a mean Dg of about μm, a Dae of about μm and density of about 0.4 g cm –3 [30] Such formulations were prepared using a two-step procedure: (1) preparation of a fluorocarbon-in-water emulsion by adding phosphatidylcholine as a surfactant with dispersal using high-pressure homogenization Then, the emulsion is combined with a second solution consisting of the API and other wall-forming materials (e.g., co-surfactants, sugars, salts, etc.), (2) spray-drying of the resulting aqueous dispersion [30] Particle Engineering for Improved Pulmonary Drug Delivery 177 Advantages of biodegradable microsphere formulations in DPIs include the following [47]: a Higher respirable fraction due to the good aerodynamic properties ascribed to the hollow porous particle design b Biodegradable, non-immunogenic and non-toxic properties c The possibility of changing the particle characteristics (e.g., morphology, density and size) 8.3.3 Spray-freeze-drying Historically, spray-freeze-drying was introduced in 1994 [48] A solution, which includes the API, is sprayed into a vessel containing a cryogenic liquid such as nitrogen, oxygen or argon This results in a quick freezing of the generated droplets, which are then lyophilized to produce porous spherical particles suitable for inhalation Despite this technique being successfully applied to produce protein particles, it still has a number of disadvantages which include the high cost, long processing time, safety concerns and possible denaturing effects of the proteins (due to the stresses associated with freezing and drying) [49] 8.3.4 Supercritical Fluid Technology A SCF is a material that can be considered to be either a gas or a liquid It has the gaseous properties in terms of penetrability but the liquid-like properties in ability to dissolve materials This technique has been driven by the need to generate particles with controlled physical properties It can provide an attractive particle engineering option to enhance aerosol performance in inhalation therapy [50] For example, engineered drug particles using SCF technology showed reduced surface free energy in comparison to micronized drug particles [51] Manipulation of the operating conditions such as temperature, pressure, nozzle flow rates and solution concentrations may enable the accurate control of particle size, shape and morphology [52] The main SCF processes can be classified as follows [53]: 8.3.4.1 Rapid Expansion of Supercritical Fluid Solution (RESS) In this method, the API is dissolved or solubilized in a SCF, then the rapid expansion of the SCF through a heated orifice leads to a high degree of supersaturation due to the reduction in the SCF density This change results in a reduction of solvation power, producing a precipitation of the drug [54] 8.3.4.2 Gas Antisolvent (GAS) Recrystallization Here the SCF functions as an antisolvent to cause precipitation within the liquid solution This technique has a number of advantages, such as the ability to control particle size of the resulting particles and producing void-free crystals [55] 8.3.4.3 Solution Enhanced Dispersion by SCF (SEDS) The SEDS method employs the same principle of the use of antisolvent in solvent-based crystallization processes [49, 53] The SCF is mixed rapidly with an organic solution containing the API, in which the latter is highly soluble This leads to a large volume expansion and reduction in the solvent density, and results in a high level of supersaturation [36] This technique has demonstrated a high capability to control the physical properties of particles [56] 178 Pulmonary Drug Delivery Salmeterol xinafoate Budesonide Lactose μm (a) (b) (c) Figure 8.5 (a) Salmeterol xinafoate (Source: Reproduced with permission from [52] Copyright © 1999, American Chemical Society), (b) budesonide (Source: Reproduced from [59], with permission from Elsevier) and (c) lactose engineered particles prepared by SCF technology (Source: Reproduced from [60], with permission from Elsevier) 8.3.4.4 Precipitation from Gas Saturated Solutions (PGSS) This technique is similar to the RESS technique because the SCF functions as a solvent rather than antisolvent in both techniques [49] In this technique, the SCF is dissolved in a molten solute before it is subjected to the rapid expansion conditions [57] and it has been used to engineer drugs such as salmeterol xinafoate [52], salbutamol sulphate [58], budesonide [59] and excipients such as lactose [60] In DPI systems, SCF technology can provide an attractive particle engineering option to enhance aerosol performance for inhalation therapy For example, both SCF–salbutamol sulphate [58] and SCF–lactose carrier [59] particles generated an improved pulmonary drug delivery of the API from a DPI A few examples are shown above in Figure 8.5 8.3.5 Pressure Swing Granulation (PSG) Technique Since the drug particles in DPI formulations are very fine, the control of their cohesiveness is a key factor in determining DPI performance One of the most effective methods in reducing such cohesiveness between particles in DPI systems is to present the particles as granules, which are easily disintegrated into aerosol form during inhalation In order to manufacture such ‘soft’ granules, the PSG technique can be applied [61] This procedure consists of two processes that are continually alternated, comprising compaction and granulation–fluidization processes Therefore, the PSG process can be considered as a cyclic fluidization and compaction process that is conducted by alternating upward and downward gas flow [62] The resulting formulated particles have excellent characteristics, rendering them attractive for use in DPI systems These properties include ideal size distributions, the generation of high fine particle fractions (FPFs), the required granule strength for ease of disintegration into aerosol form during inhalation, excellent granule dispersibility and the provision of good drug re-dispersion (i.e., generates a high percentage of the emitted dose (ED)) [61] 8.4 Engineered Carrier Particles for Improved Pulmonary Drug Delivery from Dry Powder Inhalers Maximizing the efficiency of drug aerosolization still provides a major challenge in the development of DPI formulations A slight change in particle physicochemical properties is likely to have a Particle Engineering for Improved Pulmonary Drug Delivery 179 considerable effect on drug aerosolization behaviour Thus, the use of suitably engineered particles might be an essential factor for improving DPI performance Several techniques have been described to achieve this outcome including antisolvent crystallization [63], batch cooling crystallization [64] and freeze-drying [65] These methods were used to modify two common carriers, lactose and mannitol particles, to improve the aerosolization of API from DPI formulations For example, antisolvent crystallization techniques using binary non-solvents including ethanol–butanol, ethanol–acetone and acetone–butanol produced lactose particles which when incorporated into DPI formulations of albuterol sulphate lead to an enhanced aerosolization performance [66–68] In comparison to commercial lactose, engineered lactose particles were less elongated and more irregular in shape with rougher surfaces In addition the generated lactose also contained a higher fine particle content and displayed a higher porosity These particles appeared as ‘secondary’ particles comprised of smaller ‘primary’ subunits having different sizes and morphologies, according to the type of non-solvent used during crystallization Moreover, the commercial lactose employed as a comparator was in 𝛼-lactose monohydrate form (Chapter 7), whereas engineered lactose particles were mixtures of 𝛼- and 𝛽-lactose [67] When the volume ratio of non-solvent used during crystallization was changed, the amount of amorphous, 𝛼- and 𝛽-anomer content of lactose was altered and such a strategy could be employed to optimize the aerosolization performance of lactose in the DPI formulation containing albuterol sulphate [66] In a further study, it was shown that not only was the efficiency of aerosol delivery dependent upon the non-solvent type employed but also upon the degree of saturation of lactose solution used during crystallization [63] If the crystallization procedure is controlled, lactose particles may be engineered with more predictable aerosolization properties These findings have been extended from lactose to mannitol, when the latter was identified as providing a possible improved alternative excipient in DPI formulation The morphology of mannitol particles was dependent on the manufacturing technique employed (Figure 8.6) The efficiency of drug dispersion from powders containing crystallized mannitol was influenced by the proportion of water present in the acetone or ethanol non-solvent used in the crystallization procedure [69, 70] However, regardless of the ratio of acetone–water or ethanol–water used in the recrystallization procedure, all crystallized mannitol carriers showed better performance than commercial mannitol when incorporated in DPI formulations [69, 70] Solid-state analyses demonstrated that all mannitol samples were crystalline with no detected amorphous content A change in the ratio of acetone–water or ethanol–water led to samples of mannitol with a different polymorphic content [69, 70] Formulations containing mannitol crystals grown in solutions having a lower supersaturation (20%, w/v) produced higher FPF of the API in comparison to that from formulations which incorporated mannitol crystals grown from high supersaturation (50%, w/v) (i.e., 31.6 ± 2.3% vs 14.2 ± 4.4%) This was attributed to the elongated habit, smoother surface and higher ‘intrinsic’ fines content of the former formulations Although freeze-dried mannitol did not produce a powder with a smaller geometric size than commercial mannitol, a smoother surface morphology resulted (Figure 8.6) The use of freezedried mannitol generated the weakest salbutamol sulphate–mannitol adhesive forces within the powder mix, whereas commercial mannitol generated the highest salbutamol sulphate–mannitol adhesive forces It was shown that the smoother the mannitol surface the weaker the salbutamol sulphate–mannitol adhesive forces [64] However, mannitol-containing products with higher powder porosity and weaker salbutamol sulphate–mannitol adhesive forces generated a higher FPF of salbutamol sulphate It was concluded that the freeze-drying of aqueous mannitol solutions provides an attractive approach to preparing an excipient suitable as an excipient for blending into a dry powder aerosol formulation Such a strategy might provide an avenue to generate an enhanced pulmonary drug delivery and maximal yield It is a method that is simple, reasonably cost-effective and has a low safety risk, since no organic solvents are used 180 Pulmonary Drug Delivery (a) (c) 50 μm 50 μm (b) (d) 50 μm 50 μm Figure 8.6 SEM photographs for (a) mannitol crystallized from acetone, (b) from ethanol, (c) cooling crystallized mannitol (CCM) (Source: Reproduced with permission from [64] Copyright © 2012, American Chemical Society) and (d) and freeze-dried mannitol (unpublished SEMs) In addition to ‘engineered lactose’ and ‘engineered mannitol’, an ‘engineered mannitol–lactose’ complex was another approach that has been investigated for a better aerosolization performance [71] Antisolvent crystallization has proved to be successful in preparing engineered mannitol, lactose and mannitol–lactose mixtures with improved aerosolization properties (Figure 8.7) In comparison to commercial carriers, all crystallized mannitol–lactose particles showed a more regular shape, a higher fines content and a higher specific surface area (Figure 8.7) Carriers crystallized using a higher mannitol–lactose ratio produced particles with a higher elongation ratio, a more irregular shape and a smaller true density Mannitol was altered from a spheroidal to a needle shape, but also there was a change in its polymorphic form from 𝛽-form to 𝛼-form Similarly, lactose has changed from the 𝛼-anomer form present in commercial lactose to a 𝛽-anomer form by crystallization Crystallized mannitol–lactose mixtures did not generate a markedly better aerosolization performance than either engineered mannitol and/or engineered lactose alone However, formulators can anticipate that an appropriate particle size and a suitable solid-state and morphology of lactose carrier can be generated and controlled by the judicious addition of mannitol to the crystallization medium containing lactose [71] Among all carriers investigated by Kaialy et al [64, 65], the lowest FPF of salbutamol sulphate was generated by commercial mannitol (15.4 ± 1.1%) and cooling crystallized mannitol (14.2 ± 4.4%); whereas freeze-dried mannitol produced the highest FPF (46.9 ± 3.6%) The presence of water in the crystallization of mannitol from either acetone or ethanol using a non-solvent precipitation technique has a considerable effect on the physical properties of the resultant engineered mannitol particles The initial degree of supersaturation used during crystallization of mannitol using a batch-cooling crystallization approach appeared to be a critical factor in the Future Patient Requirements on Inhalation Devices Figure 16.5 347 An outline of requirement hierarchy the formulation, etc The MRS for the device, for example, will include mechanical requirements, such as surface finish, materials, friction, tolerances, manufacturing and assembly, etc Whereas the flow resistance requirement example as given earlier can, in the MRS, be reduced to the air leakage between two assembled parts The three requirement specifications, URS, SRS and MRS can collectively be referred to as the xRS The requirement specifications, or xRS, are then used in the verification and validation work, with the final product being validated against the URS and this includes the results from user handling studies, clinical trials, etc The product is verified against the SRS meaning, including for example, performance testing which is required as a part of the CMC work The SRS verification can only be carried out using the whole product The separate modules, for example specifications relating to say the device or formulation, are verified against the MRS Here the device can be tested without the formulation and the formulation without the device Such tests can include mechanical robustness, drop tests, opening force, etc In a similar way to the device, the formulation module can also be tested separately, with suitable tests including the assessment of API homogeneity within the powder blend, flow ability, solid-state characterisation after micronisation, etc 16.3.2 Developing the Requirements A URS for a new inhalation product should articulate the needs of all the customers The customer definition as indicated previously, includes, not only the users and patients, but also healthcare professionals, regulators and payers However ‘internal customers’ also should be considered in the customer definition and these include personnel within operations, marketing, CMC development as well as the clinicians who will conduct the clinical trials (Figure 16.6) The production of a good URS is a key activity in the development of an inhalation product and also provides a great challenge It is important that the URS is comprehensive, that all the requirements are compatible and all the implications of the requirements are well analysed and understood Just as it is challenging to balance the requirements of different users, it is equally hard to accommodate all of the different customer requirements The conflicting requirements of the user were alluded previously (Section 3); the other customers will in many cases also have additional very conflicting requirements When a (high level) URS 348 Pulmonary Drug Delivery Figure 16.6 Extended customer definition is drafted, a number of specific technical questions have to be answered to select the appropriate technical solutions Such questions include for example: ‘dry powder inhaler or pressurised metered dose inhaler?’, ‘active or passive?’, ‘electronic or mechanical?’, ‘pre-metered or reservoir?’, ‘simple formulation or advanced formulation?’, ‘large dose or small dose?’, ‘RH protection or not required?’, ‘few user steps or many user steps?’, ‘dose counter or dose indicator?’, as well as many more questions The answers to these questions provide the technical framework that will ultimately define the product The xRS always has to meet the appropriate regulatory requirements Most of the regulatory requirements are addressed in the SRS, which describes the performance of the product The regulatory requirements differ from country to country and it is therefore important to define which market is to be targeted While targeting a global market all the requirements from the major regulatory agencies must be included This means primarily those imposed by the FDA (Food and Drug Administration, USA) and EMA (European Medicines Agency) but if other markets such as Japan, China, India and South America are targeted, the local regulatory requirements must also be taken into account A global market should be in mind, and then a simplified approach is to develop the inhaler device according to the FDA guidelines, [7] but to incorporate adjustments, when needed, for local requirements Independent of the intended market, the device should always be designed according the ISO 20072 standard [8] Despite the DPI, technically not being a medical device, ISO 13485 should be used in the device development [9] stage since the standard provides a well-structured and well-documented development method The regulatory requirements have a strong focus on patient safety and consistency of performance and function The patient should always get the same dose irrespective of the manner in which the inhalation product is used and conditions under which it has been stored The regulatory requirements drive the complexity and quality standards of the final product When designing the mechanics of an inhalation device, there are two types of requirements to consider One type is the functional requirement, that is, the mechanical function of the inhalation device This requirement comprises pass or fail tests, since either the inhalation device fits together and works according to specification or it does not The mechanical function can be tested and verified without the formulation and if the design fails these tests, the product cannot be approved and launched In order to reach a high process capability (as measured using the process capability index (Cpk)), which is desirable from a manufacturing and cost point of view, the tolerances should be as wide as possible (Figure 16.7) The device has to be designed to work according to the specifications, even with parts at the far end of the tolerance interval Future Patient Requirements on Inhalation Devices Figure 16.7 349 The conflicting requirements of an inhalation product (Cpk is the process capability index) The other set of requirements relate to performance and performance uniformity requirements Performance requirements must be tested with the formulation and they include, for example, delivered dose uniformity, respirable dose uniformity, chemical and physical stability, etc The actual value in the requirement is not absolute and is a matter for clinical trials and discussions with regulatory agencies There are guidelines to adhere to but many performance requirements are not covered in the guidelines [7] In general, the performance requirements focus on uniformity and robustness and the release testing of a product batch must show a performance within an acceptance range So as to fall repeatedly within this range, a very uniform and robust product is needed, a high level of uniformity in performance often being closely coupled to tight tolerances There is an obvious conflict emanating from the two sets of requirements For instance, some dimensions in the inhalation device require one tolerance for the mechanical function and one tolerance for the performance For example, the functional tolerance might have a Cpk of 1.5, which would correspond to the process capability of a mechanically functioning inhalation device, that is, with no formulation included and no pharmaceutical performance tested This tolerance level might present a potential variation in one specific dimension but such a variation in dimension could, however, lead to a high variability in performance Therefore, as an example, the variation could be in the diameter of a hole, which despite having no mechanical function governs the dispersion of the formulation and the inhalation resistance Hence, in order to achieve acceptable performance uniformity this tolerance might have to be tighter, perhaps decreasing the Cpk to say 1.2 It could be the case, that the uniformity might be improved even more, decreasing the Cpk to 1.0 However, a low Cpk will lead to a low yield and high manufacturing costs and those costs will be reflected ultimately in the price of the product This higher cost will eventually be recouped either by the producer accepting a lower profit margin or an increased charge to the payer The sponsor is thus facing a delicate trade-off between performance and cost If not handled correctly, the need for such trade-off may become apparent only very late in a development project Traditionally, in developing a device, there is a point when the design is becoming ready for high volume manufacturing, that is, multi-cavity injection moulding and automated assembly At this time a design for manufacturing and a design for assembly exercises are performed 350 Pulmonary Drug Delivery together with various suppliers In these activities, critical to function dimensions are identified and the design is optimised to minimise the impact of these dimensions and to define the tolerances achievable At this stage, it is very difficult and costly to make any major changes to the device since such changes are likely to have an obvious impact on performance The best approach to avoid a conflict between the two sets of requirements is to very early in the development process have such avoidance as a clear design strategy All various dimensions and features should be assessed in terms of their impact on the performance and function The performance-driving dimensions and features should be designed with manufacturing and process capability in mind An early involvement of operations or the injection moulding supplier can be of great benefit The supplier can at an early stage provide valuable insight into various challenges in injection moulding and assembling the device So as to both mechanical and performance considerations are taken into account at an early stage, it is important to employ staff that has the competence to combine these two sides of development [10] 16.4 Product Development The requirements, xRS, are intended to provide a fixed target and clear objective for the development In an ideal case, the requirements are defined before the technical development and design starts and are unchanged throughout the development time The various prototypes are then verified against the SRS and MRS after each development step and the product is ultimately validated against the URS This ideal, however, is never achieved in reality During the development of an inhalation product, the requirements are being constantly updated and changed, as a consequence of necessity to manage various technical challenges or due to intellectual property reasons The changes can also be driven by change of scope or market needs When the set of requirements are constantly changing, the development process must be adapted promptly to these conditions A very elaborate and comprehensive approach is to use a method called redundancy-based development (RBD) [6] Some of the key aspects of this method are described as follows so as to demonstrate the approach by which an appropriate project management strategy can greatly simplify the development, and in doing so, save both time and money If the project plans include contingencies and strategies, then it can be possible to handle the inevitable and unknown challenges and projects may then be delivered on time and on budget During development, the performance of the final product must be predicted using prototypes and modelling Traditionally, the formulation is developed by one team and the device by another but then later at a different stage in development the formulation is tested together with the device A challenge with this approach is that if the device and formulation are developed in parallel and independently, it is hard to ascertain what contributes to the performance If the latest version of the device is tested with the latest version of the formulation, it is impossible to tell if the new device design or the new formulation has contributed to the improved performance It could be that the latest change to the formulation actually makes it perform worse than the previous formulation but the improved device might deaggregate the formulation much more effectively and therefore disguise any flaws in the newer formulation In order to address this, a prototype strategy should be adopted where a key element is the use of reference prototypes (Figure 16.8) [11] As an example of this approach, a group of prototype formulations could be developed, mapping out different extreme properties a formulation may have, according to the specifications For example, one formulation could have a high API load, one formulation could have a very low API load, another formulation may have an API that is very prone to electrostatic charging, etc These formulations are then routinely used in all device development and testing and by doing this there are always several fixed points of reference to compare the latest device versions against The standard device prototypes should contain the key features of the final device in terms of formulation emptying, Future Patient Requirements on Inhalation Devices Figure 16.8 351 An outline of prototype strategy deaggregation, etc These standard device prototypes should be easy to fill and handle and should be injection moulded and available in great quantities, so as to avoid time-consuming cleaning and handling It can be worthwhile to develop a simple filling rig or tool to facilitate easy and reproducible filling of formulation into the device prototypes All formulations are then tested using these standard device prototypes Similarly, device prototypes can be manufactured for the development of the filling equipment In this case, standard formulation prototypes are used together with standard device prototypes A similar approach can also of course be taken for other types of development, for example, some process development This modular approach requires that the MRS is comprehensive and clear on the interfaces between different modules This is to allow efficient testing using reference prototypes Treating the modules as independent entities defined by the MRS and tested using reference prototypes provides a flexibility and robustness that can ably handle changes to the requirements and various technical challenges that are experienced 16.5 Conclusions When investing in the development of a new inhalation product, careful attention must be given to the URS The new inhalation product must be competitive not only in function and performance but also in the cost The URS provides definition of the product and will ultimately decide its commercial success The needs and expectations of all potential customers must be combined The term ‘customers’ includes: patients, payers, regulatory bodies, clinicians, manufacturers and suppliers This has to be combined with the performance and quality required to have a competitive product and efficacious therapy The intended patient population is now, in many ways, different and more diverse than the traditional asthma patients A major patient group today consists of patients suffering from COPD, who first start to use an inhaler at a more advanced age and thus have different expectations and needs User 352 Pulmonary Drug Delivery studies have shown that patients value feedback features the highest Other highly ranked requirements such as good hygiene characteristics and ergonomics are often in conflict, with less specific requirements based on perception To develop an inhalation device that meets all requirements is obviously impossible An option is to develop a range of devices to target specific patient groups, which will be significantly more costly and resource demanding If a single device is to be developed for all groups, the perception requirements should be played down in favour of interface and use requirements The voice of all the customers, when comprehensively collated in a URS, presents a catalogue of features, functionalities and requirements that are frequently mutually conflicting When compiling a URS, all patient-specific requirements must be weighed against other customer requirements from, for example, regulatory agencies, marketing, operations and also performance requirements This list of requirements drives the complexity of the device and ultimately the cost One key conflict is between mechanical robustness and manufacturing capability and the uniformity of the pharmaceutical performance High performance uniformity requires tight tolerances, which in turn leads to lower yield and more costly manufacturing The final cost of the product must be carefully balanced against the payers’ level of acceptance The development of an inhalation device poses many severe challenges Most of the challenges have the origin in the complex interaction between different parts of the inhalation product In order to keep down the development costs and minimise the project delay, it is important to have a thorough understanding of the inhalation product This requires a comprehensive combination of skills including those associated with the disciplines of pharmacy, engineering, chemistry and physics A good understanding of the regulatory requirements together with clinical and pharmacological experience is also very valuable This required skill base should be considered when forming project teams [10] A key challenge is to also set up a relevant and comprehensive URS for the inhalation product It is time well spent to have a thorough analysis of various consequences of each requirement An incompatible set of requirements can have tremendous ramifications on the development The consequences may not become obvious until late in the development process and these can then lead to extensive redesign and delays References Bechtold-Peters, K., Luessen, H (2007) Pulmonary Drug Delivery, Editio Cantor Verlag, Aulendorf Newman, S (2009) Respiratory Drug Delivery: Essential Theory and Practice, Respiratory Drug Delivery Online, Richmond WHO fact sheet Fact sheet No 307, www.who.int/mediacentre/factsheets/fs307/en/ World Health Organisation (2007) Global Surveillance, Prevention and Control of Chronic Respiratory Diseases: A Comprehensive Approach Rhodes M (2013) Complete the cycle: GSK’s Inhaler Recycling Programme Management Forum Inhaled Drug Delivery London Lastow, O (2012) Redundancy-based development (RBD), Inhalation Magazine, February 2012 FDA (1998) Draft Guidance for Industry: Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products ISO 20072 Aerosol Drug Delivery Device Design Verification: Requirements and Test Methods ISO 13485 Medical Devices – Quality Management Systems – Requirements for Regulatory Purposes 10 Leiner, S., Parkins, D., Lastow, O (2015) Inhalation Devices and Patient Interface: Human factors AAPS Journal, 1–5 (DOI: 10.1208/S12248-015-9717-9) 11 Lastow, O., Svensson, M (2014) Orally Inhaled Drug Performance Testing for Product Development, Registration, and Quality Control J Aerosol Med Pulm Drug Deliv., 27, 1–7 Index A549 alveolar epithelial cells 132 Absorption drugs 2, 4, 5, rate Active devices 38, 39, 42, 53 Active pharmaceutical ingredient (API) 124, 129–31, 134, 135 Adherence 342, 343 Aerodynamic diameter 36, 44, 49, 51, 176 Aerodynamic particle size 43, 51 Aerodynamic size distribution 51 Aerosol deposition 2, air flow rate 7, Brownian motion diffusion 4, 5, impaction 5, interception 5, sedimentation 5, 6, 11 Aerosolization 126, 129–31, 133–5, 173, 174, 176, 178–84, 186–90, 193 antisolvent crystallization 173 Aerosols 130, 134, 225 AFM see Atomic force microscope (AFM) Age 64, 66–8, 70, 71, 80, 81 Agglomeration 288 Aggregation 288 Air classifier technology 38 Air-jet nebuliser 246, 247, 249 Airway(s) anatomy 2, caliber 3, 13 cartilage conducting geometry 2, 8, 13 respiratory Airway cells basal ciliated columnar 3, Clara goblet Albuterol sulfate 41 AlveofactⓇ 125 Alveolar cells 3, epithelium 3, 4, macrophages 3, 4, 10 surface area Amikacin 128, 131, 132, 136 Amorphization 88, 94, 99, 103–5, 110, 112 Amphotericin B 93, 106, 107, 109, 128, 134–6 Analytical methods 331 Analytical target profile (ATP) 331, 332 Anatomy 64–7 Angiogenesis 269–76 Antibiotics 48, 53, 225 Antibody 274–8 Anticancer 93, 95, 99 Antifungal 93–5, 98, 99, 101–7, 109, 111 API see Active pharmaceutical ingredient (API) Apoptosis 271–8 Aptamer 275–6 Asthma 10, 11, 340, 351 Atomic force microscope (AFM) 202–6, 208, 211–13 Atomic force microscopy 52 Pulmonary Drug Delivery: Advances and Challenges, First Edition Edited by Ali Nokhodchi and Gary P Martin © 2015 John Wiley & Sons, Ltd Published 2015 by John Wiley & Sons, Ltd 354 Index ATP see Analytical target profile (ATP) Automated assembly 346, 349 Bacteriophages 45 BCL2 mRNA 133 Beclometasone dipropionate 225, 228–9, 236 Beclomethasone dipropionate 87, 93, 94, 100, 106, 107 Beta-adrenergic lung receptors 10 Bile salts, cholate 93, 96, 102, 103, 107, 109 Biodegradable 47, 48 Biopharmaceuticals 302, 303, 305, 306, 312, 313 Blend color data 291 Blend homogeneity 331 Blend lightness 293 Blend pigmentation 287 Box–Behnken design (BBD) 328 Box–Wilson design 328 Bronchi/bronchioles 2, 3, Bronchitis 10, 11 Broncho-alveolar lavage 87, 92, 93, 108 Budesonide 93, 94, 100, 103, 106, 129, 130, 134, 136, 173–5, 178, 184, 189–92, 194, 227, 236 Calu-3 97, 98, 107, 109, 127, 130 Cancer molecular markers (CMMs) 271–6 Capillary endothelium Capreomycin 252, 253 Capsule-based device 246 Carrier 124–6, 129–31, 133, 135, 136, 172, 174–6, 178–84, 186–9, 191, 193–7, 206–10 Cartesian 287 Cascade impactors 51, 52, 227 Cathepsin L 129 Celecoxib 134–6 Celexocib (CXB) 87, 93, 94, 111 Chemistry manufacturing controls (CMC) 323, 345, 347 Cholesterol 96, 98, 108–10, 113, 126, 129, 130 Cilia Ciprofloxacin 243, 245, 254, 255, 257, 258 Clearance 49, 50 ClinoleicⓇ 134, 135 CMC see Chemistry manufacturing controls (CMC) CMMs see Cancer molecular markers (CMMs) Cocrystal 45 Colistimethate sodium 243–5, 256, 257 ColobreatheⓇ 244, 245, 256, 257 Compliance 341, 342 Compritol 888, 130 Computational fluid dynamics 39 Computed tomography 23, 24 Computer simulation and modelling 11 Conducting zone 89–91 Content uniformity 294, 297 Continual improvement 324, 329 Controlled release 49 Control strategy 324, 328, 329 COPD 225, 340, 351 Corticosteroid 93–5, 100, 103, 106, 107 Co-solvent 93, 94, 97 Cpk 348, 349 CPPs see Critical processing parameters (CPPs) CQAs see Critical quality attributes (CQAs) Critical processing parameters (CPPs) 325, 326 Critical quality attributes (CQAs) 323–6 Crystallinity 330 Crystallization 173 CsA see Cyclosporine A (CsA) Customers 346, 347, 350, 351 CXB see Celexocib (CXB) Cyanine dye (Cy5) 133 Cyclodextrin 87, 88, 94, 95, 97–9, 112 Cyclosporine A (CsA) 87, 93, 94, 97, 101, 106, 109, 126, 127, 135, 136 DDSs see Drug delivery systems (DDSs) De-agglomeration 286, 289–90, 293, 295 Deformable liposomes 124 Degree of dispersion 293 Delivered dose 345 Dendrimers 124, 305 Deoxyribonucleic acid (DNA) 132, 136 Design of experiments (DoEs) 326, 329, 332 Index 355 Design space 324, 328 Device 64, 69–75, 78, 80, 81, 340–351 Diabetes 340 Dimeric HIV-1 TAT peptide (TAT2) 132 Dipalmitoylphosphatidylcholine (DPPC) 87, 96, 108, 109, 128 Disposable device 342 Dissolution apparatus 230–233 data analysis 235–6 in the lung 224 medium 229 methods 235 testing 226 Distearoyl phosphatidylcholine 96 DNA see Deoxyribonucleic acid (DNA) Docetaxel 134 DoEs see Design of experiments (DoEs) Doxorubicin 133, 136 DPI see Dry powder inhaler (DPI) DPI devices see Dry powder inhaler (DPI) devices Drug adhesion 201, 204, 206–8, 210, 212–14 detachment 201, 207–9, 215 entrapment 201, 204, 209, 211, 213, 214 Drug delivery 172, 176, 178, 179, 182, 184, 189 Drug delivery systems (DDSs) 265–8 Dry powder(s) 308, 310 device 39–43 formulation 37, 41, 45, 48, 49, 52 inhalation 35–62 Dry powder inhaler (DPI) 37, 39, 42, 50, 67, 68, 73, 74, 125, 126, 128–30, 133, 136, 172, 178, 182, 191–7, 250, 251, 254, 256–8, 286, 288, 296, 321–32, 340, 345, 348 Dry powder inhaler (DPI) devices 171 Emulsion based 124 Energy input 293 Enhance permeation and retention 271–3 Enzymatic degradation 10 Enzymes 2, EPI see Epirubicin (EPI) Epirubicin (EPI) 131, 136 Epithelial lining fluid (ELF) 3, 90, 91, 93 Epithelial to mesenchymal transition (EMT) 266–9 ER see Elongation ratio (ER) Ethanol 93, 96, 97, 109 Ethosomes 124 Excipient 345 Excipient critical attributes (ECAs) 325, 326 ECAs see Excipient critical attributes (ECAs) Electrical impedance tomography 25 Electronic feedback 343 Elongation ratio (ER) 185 EMA 348 Emitted dose 42, 44, 51, 52 Gamma scintigraphy 127, 128 Gas exchange Gene delivery 132, 136 Gentamicin 252, 254 Glucocorticoids 10 Glucose 96 Facemask 75, 76 Failure mode effect analysis 325 FDA 348 Fenoterol 236 Fine particle fraction (FPF) 41–4, 129, 130, 133, 135, 322 Fine particles 188–9 Fixed-dose combination 41, 44, 47 Flow 184 Flunisoline 236 Fluticasone propionate 45, 93, 95, 100, 103, 236 FMEA 325, 326 Folate receptor alpha (FR𝛼) 276 Formoterol fumarate 40, 47 Formulation 340, 344–7, 349–51 Formulation development 21, 22, 31 FPF see Fine particle fraction (FPF) Fractional factorial design 328 Franz cell 233 Freeze-drying 308 Full factorial design 327 Functional lung imaging 22, 28, 30, 31 Fungizone 128 356 Index Glycerin 93, 96 Glyceryl monooleate 135 Grating interferometry 27 High gravity controlled precipitation 43 Homogeneity 293 Hood 78 Humidity 288 Hydrocortisone 236 Hydroxyapatite 43 Ibuprofen 135, 136 ICH Q8 322, 326, 328 ICH Q8 (R2) 328 ICH Q9 322, 326 ICHQ10 322, 328 Immunosuppressant 93–5, 97, 101, 104–6, 109 Impeller speed 294 Independent models difference factor 237 similarity factor 237 INH see Isoniazid (INH) Inhalation 124, 127, 128, 132–5, 286, 295–6 device 340, 352 mode Inhaled corticosteroid 46 Inhaled insulin 340 Injection moulding 349 Insulin 129, 131, 136 Interaction forces 43, 52 Interactive powder mixtures 322 Interface 69, 74, 79, 81 Interferon-alpha 131 IntralipidⓇ 134, 135 Ipratropium bromide 47 ISO 348 Isoniazid (INH) 128, 136 Itraconazole (ITZ) 87, 93, 95, 99, 101–6, 111, 131, 136 ITZ see Itraconazole (ITZ) Jet nebulizer 128 Ketotifen fumarate 129, 136 Lactose 96, 100, 104, 114, 143–69, 172, 178–81, 184, 186, 187, 189, 190, 192–7, 292, 295, 296 amorphous 146–50, 152, 153, 155–8, 161, 162 carrier 159–62 chemical forms 145 crystalline 144, 146–9, 152–6, 158, 162 differential scanning calorimetry 157–8 epimerisation 150–151 infrared spectroscopy 156–7 nuclear magnetic resonance (NMR) 153–6 polarimetry 158–9 production 145 properties 147 solid state forms 148 x-ray diffraction 152 Large unilamellar vesicles (LUVs) 126 Laser diffraction 51, 52 Lecithin 96, 99, 103, 104 Levofloxacin 243–5, 256 Lipid 124–35 Lipid nanoparticle 88, 95, 100, 110, 111, 113 Liposomes 93–5, 100, 108, 109, 111, 113, 124–9, 131, 277 Long acting beta agonist 46 Lung absorption 88–93, 97–9, 101, 102, 104, 106, 107 age difference 11, 13 anatomy circulation clearance 3, 9, 11 dimensions 2, diseases 11, 13 gender differences 11 imaging 19–34 receptors 10 residence/retention 92, 107, 111 surfactant 4, 91, 96, 98, 106–9, 113 tissue to serum concentration 92, 101, 106 tolerance 106, 108, 110–112 LUVs see Large unilamellar vesicles (LUVs) Lymphatic drainage 132 Macromolecules 302–6, 308–10, 312 Macrophage 89–93, 99, 100, 107, 108, 110, 113 Magnetic resonance imaging 24 Index Mannitol 96, 98, 102–5, 130, 132, 133, 172, 175, 179–81, 186, 188, 189, 191–4, 197 Mass median aerodynamic diameter (MMAD) 125 Material attributes 324 Mathematical models MDI see Metered dose inhaler (MDI) Mechanisms of drug absorption paracellular transcellular 6–8 transport mediated 13 Mesh nebulizer 134 Metabolism 89, 92, 93, 104 Metered dose inhaler (MDI) 50, 67, 68, 72, 323 Method operational design ranges (MODR) 331 Methyl oxides 288 Micelles 93–5, 100, 106–9, 113, 124, 131, 304 Microemulsions 124 Micronization 100, 112 Microparticles 4, 124, 126, 129, 132, 133, 305, 308, 310, 311 Milling 286, 295 Mixer behaviour 290 Mixer characteristics 290 MLVs see Multilamellar vesicles (MLVs) Modelling Higuchi 236 Korsmeyer and Peppas 236 Weibull 236 zero order 236 Models for aerosol deposition 12–13 MODR see Method operational design ranges (MODR) Module requirement specification (MRS) 346, 347, 350, 351 MRP 273–4 MRP1 mRNA 133 MRS see Module requirement specification (MRS) 99 mTc 132 Mucociliary clearance 3, 9, 11, 225 Mucociliary escalator 89–92, 100, 108 357 Mucus 91, 100, 106 function secretion Multidose device 38, 40 Multidrug resistance (MDR) 273 Multilamellar vesicles (MLVs) 126 Multi-stage liquid impinger 249 Multiunit dose device 38 Muscarinic lung receptors 10 Mycobacterium M smegmatis, 128 M tuberculosis, 135 Nanocarriers 47, 50 Nanocluster 94, 95, 100, 103, 112 Nanocomposite microparticles 308, 310 Nanocrystal 94, 95, 101, 102, 104, 112 Nanoemulsions 124, 134, 135 Nanomedicines 271–8 Nanoparticles 4, 7, 45, 47–50, 94, 95, 99–104, 110, 113, 124–6, 129, 131–5, 272–4, 305–13 Nanoparticulate 124 Nanostructured lipid carriers (NLCs) 124, 125, 129, 133, 134, 136 Nanosystems (NSs) 271–8 Nasopharynx 2, Nebulization 126–8, 130–132, 134–6 Nebulizers 67–71, 125–9, 133, 134, 340 Necrosis 274–7 Next generator impactor (NGI) 249, 258 NIH 3T3 cells 135 9-nitrocamptothecin (9NC) 127, 136 Niosomes 124, 125 NLCs see Nanostructured lipid carriers (NLCs) Nonsmall-cell lung carcinoma (NSCLC) 265–79 NSCLC see Nonsmall-cell lung carcinoma (NSCLC) Nuclear medical imaging 25 Oleic acid 96, 111 Oligolamellar (OLVs) 126 OLVs see Oligolamellar (OLVs) 358 Index O-palmitoyl mannan (OPM) 128 O-palmitoylpullulan (OPP) 128 OPM see O-palmitoyl mannan (OPM) OPP see O-palmitoylpullulan (OPP) Optimization 297 Ordered mixing/mixture 200, 206, 207, 209 Paclitaxel 88, 93, 95, 127, 131, 133, 136 PARI eFlow inhaler 127 Particle 124–6, 128–35 clearance deposition 5, 20 imaging 25 modelling 21 engineering 171, 172, 177, 178, 181, 191, 192, 250, 257 polydispersity residence time shape 185–6 size 5, 6, 288–90, 293, 329 testing 226, 227 Passive devices 38–40, 53 Passive inhaler device 250 PAT see Process analytical technology (PAT) Patient-related factors 66, 80 Patient requirements 341, 352 Pegylation 99, 100, 106–8, 110, 113 Peptides 45, 49, 50 Permeability 88–90, 92, 97–9, 107, 109, 113 Permeation enhancer 98 P-glycoprotein (P-gp) 8, 273–4 Pharmaceutical development 322 Pharmaceutical quality system 322 Phase-contrast imaging 26, 28 Phospholipase A2 106, 108 Phospholipid 91, 96, 98, 105–10, 113 Photodynamic therapy (PDT) 277 Physicochemical properties 174, 178, 181, 182, 188, 189 Physiology 64, 66, 67 Pigment 289, 296 Plackett–Burmanor and Taguchi 327 pMDIs see Pressurized metered dose inhalers (pMDIs) Poloxamer 130 Poly (DL-lactide-coglycolide acid) 45, 47–50 Polyethylene glycol 88, 93, 96 Polymer 124 Polymorphism 330 Polysorbate 96, 101, 102, 111 Polyvinyl–pyrrolidone 135 Polyvinylpyrrolidone K30 96 Porous particles 176 Povidone K25 96 Powder dispersion 36–40, 46 Pressure swing granulation (PSG) technique 178 Pressurized metered dose inhalers (pMDIs) 125, 126, 226, 229, 340 Process analytical technology (PAT) 322, 329, 331, 332 Product development 321 Product performance 345, 352 Product quality 324 Proniosomes 124 Propagation-based imaging 28, 29 Propylene glycol 93, 97, 109 Proteins 45, 49, 50 Pseudomonas aeruginosa 131 PulmicortRespulesⓇ 134 Pulmicort TurbuhalerⓇ 130 Pulmonary 302, 303, 305, 308–13 aspergillosis 128 blood circulation drug delivery 123, 125, 129, 131, 133, 134 route 124, 131, 135, 136 PulmoSphere™ 251, 254 Pulmosphere® 45, 176 Pyrazinamide 130, 136 QbD see Quality by design (QbD) QRM see Quality risk management (QRM) QTPP see Quality target product profile (QTPP) Quality by design (QbD) 321–4, 328–32 Quality risk management (QRM) 322, 325, 326 Quality target product profile (QTPP) 323, 324, 331 Quercetin 130, 136 RAW 264.7 cells 132 Index Recombinant secretory leukocyte protease inhibitor (rSLPI) 129, 136 Recommendations 69, 74, 80, 81 Redundancy-based development 350 Respirable 128, 129, 131–3, 135 dose 248, 345 fraction 249, 251, 345 particles 340 Respiratory zone 89–91 Response surface methodology (RSM) 326–8 Reusable device 342 Rifampicin 45, 48, 128, 130, 136 Risk assessment 324 Robustness 295–6 Roughness 179, 181, 189, 197 definition 200–201 macroscale 201, 205–7, 214, 215 measurement 202, 206 modification 210, 215 nanoscale 201, 202, 204, 208, 209, 213, 215 parameters 203, 204, 211, 212, 215 profile 201, 203 rSLPI see Recombinant secretory leukocyte protease inhibitor (rSLPI) RSM see Response surface methodology (RSM) Salbutamol 130, 136 Salbutamol sulphate 173, 174, 178–81, 183, 187, 188, 190, 193, 195–7, 236 Salmeterol xinafoate 46, 230 Scale of scrutiny 296 Scale up 331 Scanning electron microscope (SEM) 205, 206, 211, 212, 214, 215 SCLC see Small- cell lung carcinoma (SCLC) SEM see Scanning electron microscope (SEM) SEM images 289 S100 family proteins 134 Simulated lung fluid 52, 88, 99, 101, 104, 107 Single-unit dose device 37 siRNA see Small interfering ribonucleic acid (siRNA) SLMs see Solid lipid microparticles (SLMs) 359 SLNs see Solid lipid nanoparticles (SLNs) Small-cell lung carcinoma (SCLC) 265–79 Small interfering ribonucleic acid (siRNA) 45, 50, 131, 133, 136 Small unilamellar vesicles (SUVs) 126 Sodium cholate 131 Solid dispersion 88, 94, 95, 99, 103–6, 112 Solid lipid microparticles (SLMs) 124, 129–31, 136 Solid lipid nanoparticles (SLNs) 124, 125, 129, 131–3, 136 Solubility 224, 226 Solubility/dissolution 88, 99 Sono-crystallization 46, 47 Sorbitan 96 Soy-lecithin 130 Spacer 76, 77 Spray drying 44, 45, 47–50, 52, 174, 251–3, 255, 308–10 advantages 174 deposition 174 geometric diameter 174 Spray-freeze-drying 45, 177, 308, 309 Spray freezing in liquid 45 SRS see System requirement specification (SRS) Supercritical fluid 308, 310 Supercritical fluid technology gas antisolvent (GAS) recrystallization 177 precipitation from gas saturated solutions (PGSS) 178 rapid expansion of supercritical fluid solution (RESS) 177 solution enhanced dispersion by SCF (SEDS) 177 Surface area 187–8, 289 roughening 210, 213 smoothing 210–212 Surfactant 124–6, 128, 131, 135 SUVs see Small unilamellar vesicles (SUVs) System requirement specification (SRS) 346, 347, 350, 351 Tacrolimus 87, 93, 95, 104, 105 Targeting 265–79 360 Index TAT2-M1 132 TechnosphereⓇ 40, 41, 49 Tetrafluorothane 47 Theranostics 270–278 Thermal ink-jet 45 Thin film freezing 46 Thymopentin (TP5) 131, 136 Tight junctions Tiotropium bromide 47 TME see Tumor microenvironment (TME) Tobi podhalerⓇ 244, 245, 250, 251, 257 Tobramycin 45, 48, 244–7, 249–52, 254, 256 Tolerances 349 Topography 200, 203–5, 208, 213, 215 Trachea 2, 3, Transferrin (Tf) 276–7 Transferrin receptor (TfR) 276–7 Transporter molecules Trehalose 96 Triamcinolone acetonide 236 Trojan particles 126 Tumor microenvironment (TME) 266–79 Twin stage impinge 227–8 Tyloxapol 96 Ultrasound nebuliser 246, 247 URS see User requirement specification (URS) User feedback 341 User requirement specification (URS) 346, 347, 350–352 User studies 341, 342, 352 Validation 290 Valve holding chamber 76, 77 Van der Waals forces 176 Vesicle 124, 126 Vibrating membrane devices 248 Vibrating mesh nebuliser 245–8 Virus 45, 50 Viscoelastic layer 224 Voriconazole 46, 48, 88, 93, 95, 98, 99 Weibel model WILEY END USER LICENSE AGREEMENT Go to www.wiley.com/go/eula to access Wiley’s ebook EULA ... insulin-loaded microparticles for pulmonary delivery European Journal of Pharmaceutics and Biopharmaceutics, 20 08; 68 (2) , 191 20 0 190 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Pulmonary Drug Delivery... 42( 4), 1069–10 72 Mullin, J (1993) Crystallisation Techniques and Equipment Butterworth-Heinemann Ltd, Oxford Particle Engineering for Improved Pulmonary Drug Delivery 25 26 27 28 29 30 31 32. .. Lactose VMD (μm) 10 100 Lactose VMD (μm) MMDA GSD 3.5 2. 5 1.5 2. 8 2. 6 2. 4 2. 2 GSD 350 20 0 20 40 60 80 100 120 Lactose VMD (μm) 50 RD or ED (μg) R2 = 0.997 400 RD (μg) ED (μg) Constant K y = –0.00874x