Alternative carriers in dry powder inhaler formulations

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Alternative carriers in dry powder inhaler formulations§ Yahya Rahimpour1, Maryam Kouhsoltani2 and Hamed Hamishehkar3 1

Biotechnology Research Center and Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran Research Center for Pharmaceutical Nanotechnology and Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran 3 Pharmaceutical Technology Laboratory, Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran 2

The aerosolization efficiency of a powder is highly dependent on carrier characteristics, such as particle size distribution, shape and surface properties. The main objective in the inhalation field is to achieve a high and reproducible pulmonary deposition. This can be provided by successful carrier selection and careful process optimization for carrier modification. Lactose is the most common and frequently used carrier in dry powder inhaler (DPI) formulations. But lactose shows some limitations in formulation with certain drugs and peptides that prohibit its usage as a carrier in DPI formulations. Here, we criticality review the most important alternative carriers to lactose with merits, demerits and applications in DPI formulations.

Introduction Lactose is the most common and frequently used carrier in DPI formulations and nowadays various inhalation grades of lactose with different physicochemical properties are available on the market. A wealth of literature has been published about preparation and characterization of lactose for inhalation purposes [1–5]. But because of clinical considerations, lactose cannot be used for drug delivery to diabetic patients. Moreover, for some drugs (e.g. formoterol) or for specific applications (e.g. peptide or protein drugs) lactose monohydrate might not be the carrier of choice as a result of its reducing sugar function that can interact with functional groups of the drug or the protein [6,7]. In addition, lactose monohydrate is produced from bovine milk or with bovine-driven additives so that transmissible spongiform encephalopathy (TSE) is still an issue of concern for this compound [8]. Lactose intolerance is a problem that necessitates the patient to use lactose-free formulations [9]. It is therefore logical to look for substitute carriers that still possess the § Chemical compounds studied in this article: Lactose monohydrate (PubChem CID: 104938); D-mannitol (PubChem CID: 6251); trehalose dehydrate (PubChem CID: 7427); erythritol (PubChem CID: 222285); sorbitol (PubChem CID: 5780); raffinose (PubChem CID: 10542); maltose (PubChem CID: 6255); dextrose (PubChem CID: 5793); xylitol (PubChem CID: 6912).

Corresponding author:. Hamishehkar, H. ([email protected]), ([email protected])

positive aspects but overcome the above mentioned drawbacks of lactose monohydrate [10,11]. So, the purpose of this manuscript is to review substitute carriers to lactose in inhalable formulations, their production and the impact of their physicochemical properties on pulmonary drug dispersion and deposition. Figure 1 summarizes the chemical structure of proposed alternative candidates as carriers for dry DPI formulations.

Formulation principles of DPIs Inhaled drug delivery devices can be divided into three main categories: nebulizers, pressurized metered-dose inhalers (pMDIs) and DPIs. Each class presents unique strengths and weaknesses. Among these, DPIs appear to be the most promising for future use [12]. They are propellant-free, portable, easy to operate and low-cost devices with improved stability of the formulation as a result of the dry state [13–15]. Most DPIs are formulated as larger carrier particles blended with a micronized drug with aerodynamic particle diameters of 1–5 mm [16]. Generally, micron-sized drug particles are very cohesive and show poor flow properties; therefore, utilization of carrier materials improve drug particle ‘flowability’, dosing accuracy and minimize the dose variability observed with drug formulations alone as well as increasing the dispersing properties of cohesive dry particles during emission [7,17,18]. Moreover, DPIs usually have

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OH CH2OH OH O OH

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α-Lactose monohydrate

H

H H CH2OH

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2H2O OH

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α,α-Trehalose dihydrate

D-Mannitol HO

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OH HO H

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O H O OH

Erythritol

Sorbitol

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FIGURE 1

Chemical structures of alternative candidates for carriers in dry powder inhaler formulations.

very small therapeutic doses (e.g. between 20 mg and 500 mg of corticosteroids for asthma therapy), and thus the carrier provides bulk, which improves the handling, dispensing and metering of the drug [19]. Figure 2 schematically shows the role of the carrier in DPI formulation. Carrier and drug combine based on ordered mixing to obtain predictable component distribution. An adhesive mix of drug on carrier is achieved as result of drug particles being smaller than the carrier [20]. Then, to generate the aerosol, the patient’s inspiratory flow can be used to move the particles into the lung. While the patient activates the DPI and inhales, the introduced air into the powder bed causes shear and turbulence; therefore, the static powder blend becomes fluid and enters the patient’s airways [21]. During insufflation, the drug particles release from the surface of the carrier particles and are drawn deep into the lungs, meanwhile the larger carrier particles impact the oropharynx and are cleared [22,23]. The interparticulate forces between drug and carrier are a challenge in the performance of DPIs, because a strong force is needed to resist segregation before application but, by contrast, release of sufficient drug from the carrier surface during inspiration and/or aerosolization

Carrier

Mixing

must be permitted [24]. Unsatisfactory drug detachment from the carrier surface is one of the main explanations for the poor aerosolization efficiency encountered with DPIs [25]. Therefore, the carrier particle forms an important constituent for the development of DPIs and every change in the physicochemical properties of the carrier has the potential to alter the drug aerosolization profile [26]. The other important issue is that the generalization of the performance of one carrier for different drugs is not possible. If the drug is changed, the influence of carrier on drug inhalation performance is also changed. Therefore, the attempts of formulators in investigating the various carriers for optimized drug pulmonary deposition are indeed needed [27]. Carrier particles should have several features including physicochemical stability, biodegradability, biocompatibility and compatibility with the drug substance. They must be available and economical as well [28]. Consequently, the efficiency of a DPI formulation is extremely dependent on the carrier characteristics, thus the selection of carrier is a crucial determinant of the overall DPI performance [19]. Figure 2 shematically ilustrates the DPI elements, formulation process and inhalation performnace.

Inspiration

Oropharyngeal deposition

DPI formulation Drug

Pulmonary delivery Drug Discovery Today

FIGURE 2

Schematic representation of dry powder inhaler system: formulation, separation within inspiratory flow, oropharyngeal and pulmonary deposition of the drug. 2

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Mannitol Mannitol, a hexahydric alcohol, has been mainly used as a pharmaceutical excipient. Its potential use as a carrier for aerosol delivery has been reported [15,29]. Mannitol is not a reducing sugar, is less hygroscopic than lactose [30] and gives a suitable sweet aftertaste, which has a benefit to patients confirming them that a dose has been properly administered [31]. Mannitol proved to be the most promising candidate for this application compared with the more hygroscopic sugar alcohols such as sorbitol, xylitol and maltitol. D-Mannitol is currently marketed in some countries as a pulmonary diagnostic DPI aerosol (AridolTM) and as a therapeutic dry powder inhalation aerosol for the treatment of cystic fibrosis and chronic bronchitis (BronchitolTM), which were recently approved by the FDA and the European regulatory committee, respectively [32]. The spherical mannitol particles used in AridolTM were produced by a spray-drying technique [33]. A DPI formulation for inhalation of ciprofloxacin hydrochloride (an antibacterial fluoroquinolone) was prepared by its co-spray-drying with different percentages of mannitol. The combination formulation containing 50% (w/w) mannitol showed the best inhalation performance, good stability and the lowest particle cohesion (as measured by colloid probe microscopy). It was proposed that the combination of co-spray-dried mannitol and ciprofloxacin from a DPI is an attractive approach to promote mucous clearance in the respiratory tract while simultaneously treating local chronic infection, such as chronic obstructive pulmonary disease and cystic fibrosis [34]. Spray drying was used to prepare several types of mannitol differing in shape and surface roughness. In this study, besides introducing the spray-drying method as a proper technique for the preparation of mannitol as a carrier for inhalation purposes, it was concluded that the highest fine-particle fraction (FPF) was achieved with carrier particles of spherical shape and a rough surface [35]. Despite the above mentioned study, in another report it was shown that the use of elongated mannitol as the carrier particle produced improved DPI performance [36]. It was also indicated that mannitol particles crystallized from either acetone or ethanol (a-mannitol) showed the best aerosolization performance, whereas the poorest aerosolization performance was obtained from commercial mannitol (b-mannitol) [36]. The same research group in another study again reported the better inhalation performance of salbutamol sulfate from elongated mannitol. In this study mannitol was crystallized from different binary mixtures of acetone:water, and its carrier role in DPI formulations of salbutamol sulfate was investigated [31]. Mannitol particles, produced by spray drying, have been used commercially (AridolTM) in the bronchial provocation test (i.e. the mannitol particle itself as the active ingredient not as a carrier). In a study, confined liquid impinging jets (CLIJs) followed by jet milling were applied and introduced as an alternative method for spray drying for inhalable powder preparation. Although the inhalation performance of mannitol particles prepared by the CLIJ method was not higher than those prepared from the spray-drying method (FPF of 30% for particles prepared by CLIJ method compared with 47% of those prepared by spray-dying method), the CLIJ method offered several other advantages. The main advantage of the CLIJ method is that it can be scaled up with an acceptable yield because the precipitate can be largely collected and recovered on a filter, compared with the

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spray-drying method, which has a low collection efficiency for fine particles below 2 mm [33]. Lactose, mannitol and glucose were used as the carriers in the formulations of inhalation powders of budesonide and salbutamol sulfate. The highest respirable fraction of drugs was achieved when mannitol was used as the carrier [37]. Multisolvent recrystallization technique has been used to produce mannitol crystals appropriate for enhanced aerosolization efficiency of salbutamol sulfate. The FPF increased from 15.4  1.1 to 45.8  0.7% when the commercial mannitol was replaced by mannitol crystallized from ethanol:water (90:10). This improvement was attributed to the presence of elongated mannitol crystals in the DPI formulations [38]. In another study the superior DPI performance of freeze-dried mannitol in comparison with spray-dried mannitol and commercial mannitol was shown by comparing FPF of salbutamol sulfate accompanying these carriers, which were 47, 24 and 17%, respectively [39]. It was suggested that freeze drying aqueous mannitol solutions is a promising approach to prepare dry powder aerosol formulations owing to its advantages such as enhanced pulmonary drug delivery, high production yield, simplicity, cost–benefit and technique safety as a result of the lack of organic solvents in the final product [39]. In a recently published study, mannitol crystals were modified with a novel approach entitled ‘treating excess commercial carrier particles in a saturated solution of the same carrier’ to improve carrier performance in drug delivery to the lungs [40]. In this proposed method commercial mannitol particles were treated with aqueous mannitol supersaturated solutions under stirring for either 24 hours or 48 hours. The engineered mannitol particles showed better aerosolization performance of the model drug, salbutamol sulfate, which was attributed to surface modification of mannitol. Mannitol–lactose crystallized carrier particles were prepared in different ratios using antisolvent precipitation techniques and compared with mannitol or lactose alone in terms of in vitro DPI performance of salbutamol sulfate. By reporting at least two times higher FPF for composite carriers than lactose or mannitol alone, the simultaneous crystallization of lactose–mannitol was proposed as a new approach to improve the performance of DPI formulations [41]. Composite mannitol particles (made of 3 mm subunits) were studied as a carrier in the formulation of DPIs for a model drug (salbutamol sulfate). This carrier showed more than three times higher drug inhalation efficiency than regular sieved mannitol of the same size (i.e. 63–90 mm) that was attributed to improved carrier homogeneity and reduced drug–carrier adhesion observed in the composite carrier [42]. The composite approach provides a new insight into designing carriers for application in the formulation of DPIs with a wide range of candidate active agents for pulmonary drug delivery. In a very recent study, drug (meloxicam) crystals were embedded in mannitol accompanying different polymers (polyvinyl alcohol or polyvinylpyrrolidone) or a nonionic surfactant (Tween1 80) and/or an amino acid (leucine) to develop respirable mannitol-based microcomposites for pulmonary delivery. Addition of polymers improved drug dissolution and inhalation efficiency of meloxicam, whereas the drug–mannitol microcomposite without additive presented acceptable results (10 and 20% lower values in drug dissolution and inhalation efficiency, respectively). Although addition of Tween1 improved drug dissolution significantly, the inhalation efficiency of drug declined

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drastically attributed to the surface-caused aggregation of the particles [43]. Finally, authors claimed that the developed meloxicam–mannitol–polymer–leucine microcomposite system is applicable for anti-inflammatory and antifibrotic local pulmonary therapy but they did not explain what the destiny of polymer accumulation in the lungs after multiple-dose therapy would be. Inhalation of proteins prepared by spray drying is a promising route of administration as an alternative to injection but the crucial issue is to preserve protein structure unchanged. Mannitol is utilized regularly as an excipient during drying of proteins [44– 46]. In a study, stability of a model protein (lysozyme) co-spraydried with a combination of mannitol/sorbitol and mannitol/ trehalose was compared with carriers alone [47]. Protein biological activity measurement proved that the mixture of mannitol/ trehalose provided the highest retained activity for protein after storage at elevated temperature and relative humidity. This work indicated the importance of careful selection of mixed excipient systems for protein stabilization. In a very recently study, Young and co-workers demonstrated that mannitol can delay the clearance of ciprofloxacin HCl from the lung epithelia via the increase in apical surface liquid volume and subsequent reduction in pH. Thus, it might be useful to maintain high concentrations of antibiotics for its antimicrobial efficacy and reduction in dosing frequency [48].

Trehalose Trehalose dihydrate is a disaccharide and crystalline hydrate like lactose. However, trehalose dihydrate is a nonreducing sugar and lactose monohydrate is a reducing sugar. Reducing sugars participate in solid-state chemical degradation by the Maillard reaction with certain types of small molecular weight drugs (such as formoterol and budesonide) and polypeptide- or protein-type drugs. Therefore, some attempts have been carried out on the application of trehalose in the formulation of DPIs. In a study, trehalose was used as a carrier for DPI formulation of albuterol sulfate, ipratropium bromide monohydrate, disodium cromoglycate and fluticasone propionate [32]. The highest inhalation performance was reported for the blend of albuterol and ipratropium with trehalose dihydrate in comparison with lactose monohydrate and mannitol [49]. Spray-dried inhalable trehalose microparticulate and/or nanoparticulate powders with low water content were successfully produced by spray drying their methanolic solution under various conditions, and were fully characterized regarding water content, morphology and crystallinity [50]. The authors claimed that the inhalable trehalose microparticles and nanoparticles with different particle morphologies were successfully produced for the first time via a novel advanced spray-drying technique. However, no therapeutic indication can be imagined for inhalable trehalose particles. This technology could be useful in co-spray-drying with the candidate drugs for pulmonary drug delivery if it would be applicable. Suitable particle size, good dispersibility and solid-state properties of salbutamol sulfate were achieved by co-spray-drying with trehalose– leucine combination in comparison with other excipients such as mannitol, glycine and alanine. Mannitol–leucine combination resulted in better in vitro aerosolization of drug but mannitol showed some degree of recrystallization. Trehalose–leucine mixture appears to have a good potential to be developed into a 4

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universal carrier platform for pulmonary delivery of potent biomacromolecules [51].

Erythritol Erythritol, a meso-compound of 1,2,3,4-butanetetrol, is a naturally occurring sugar alcohol existing in various fruits and fermented foods, as well as in body fluids of humans and animals. Industrially, it is prepared from glucose fermentation [28,52]. Erythritol has been administered as a suitable excipient in pharmaceutical formulations because of its thermal stability, very low hygroscopicity [53], sweet taste, low toxicity [54] and high compatibility with drugs such as glucagon peptide [55] and acetaminophen [56]. Owing to the above desired characteristics, erythritol was recently entered in the European Pharmacopoiea [57]. Endo et al. used erythritol as the carrier in a DPI formulation of glucagon, a key regulatory element of glycogen metabolism. This hormone has been restricted to parenteral administration. In vitro and in vivo studies indicated suitability of erythritol for application in DPI formulation. Moreover, it was claimed that this dry powder inhalation of glucagon can be administered for the clinical treatment of hypoglycemia, and the maintenance of normal circulating glucose levels in patients with total pancreatectomy [55]. In a comparative study, erythritol and lactose monohydrate were used as carriers in DPI formulation of salbutamol sulfate. Drug–carrier adhesion was measured using atomic force microscope colloid probe technique and showed a higher adhesion force for erythritol than lactose. Consequently, lower inhalation performance of salbutamol sulfate resulted from DPI formulations containing erythritol in comparison with lactose. However, it was concluded that, even though erythritol can show a reduced DPI functionality, it can offer some potential advantages in terms of its reproducible chemical structure and stability [57].

Sorbitol Reducing sugars such as lactose can have an impact on the stability of proteins and peptides [58,59]. Actually, the use of lactose with protein powders can cause a reaction with lysine residues present in protein, generating lactosylated protein molecules [60]. In this case, polyols such as sorbitol can play a crucial part in the formulation of respirable protein powder. Sorbitol can also serve as a stability enhancer during processing. It was reported that the stability of interferon-b to jet milling, required to produce a respirable powder, was found to be dependent upon the presence of sorbitol in the formulation [61,62]. Sorbitol showed a comparable inhalation outcome for salbutamol sulfate with lactose and mannitol but failed to produce efficient dispersion of the drug (FPF less than 10%) [63].

Other carriers Recently, the feasibility of using pollen-shaped hydroxyapatite particles as the carrier in DPI formulation of budesonide has been investigated. The hydroxyapatite carriers showed better ‘flowability’ and higher capability of drug attachment than commonly used lactose carriers with a similar size range. Consequently, DPI formulations with hydroxyapatite carrier gave higher drug emission and respirable fraction than traditional lactose carriers [64]. Many different non-lactose carriers have been investigated, such as cyclodextrins, dextrose, glucose monohydrate, maltitol, maltose,

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raffinose pentahydrate and xylitol. Anhydrous glucose is already used in the marketed product Bronchodual1 (Boehringer) [65]. Sucrose, trehalose and raffinose are nonreducing sugars and as such have the advantage that they will not undergo the Maillard browning reaction with proteins [66]. However, in contrast to lactose monohydrate, which was found to only take up moisture on its surface, a main difficulty with these sugars (especially with the more hygroscopic substances – sorbitol, maltitol and xylitol) has been attributed to their sensitivity to humidity. In fact, the capillary forces, arising from the dynamic condensation of water molecules onto particle surfaces, seem to be less prominent with mannitol and lactose as carriers, probably because of their less hygroscopic characteristics than the other carbohydrates [67,68]. The effect of storage at an elevated humidity [75% relative humidity (RH)] on the aerodynamic properties of salbutamol blended with different carriers (alpha lactose monohydrate, sorbitol, maltose and dextrose) was investigated [67]. Before exposure to 75% RH, the lactose blend was found to give the highest FPF of salbutamol (37%), followed by sorbitol, dextrose and maltose blends (29, 25 and 13%, respectively), determined by multistage impinger. After 6 days of exposure to 75% RH just a small reduction of salbutamol FPF was observed from the lactose blend but there was a drastic decrease in salbutamol FPFs from other blends. It was found that the changes in FPF of drug had a direct relationship with carrier water uptake. The lactose blend adsorbed only 0.4%, whereas 11.3, 26.1 and 28.9% water uptake was found for dextrose, sorbitol and maltose, respectively. The final conclusion of this study was that lactose monohydrate is a far better carrier than other sugars investigated in this study even before exposure to humidity. However, it was proposed that the difficulties arising from their hygroscopicity can be resolved by adding an ultrafine hydrophobic excipient to the powder blend [29]. Comparing the different forms of mannitol, lactose and maltitol mixed with terbutaline sulfate resulted in higher FPF for crystallized mannitol mixed with terbutaline sulfate [30]. Hooton et al. used beta cyclodextrin, lactose, raffinose, trehalose and xylitol for formulation of salbutamol sulfate DPI and applied the cohesive–adhesive balance technique for analyzing quantitative atomic force microscopy measurements to interpret the inhalation behavior of drug. The rank order of the FPF of the salbutamol-sulfate-based carrier DPI formulations was beta cyclodextrin > lactose > raffinose > trehalose > xylitol, which had a linear correlation with the cohesive:adhesive ratios of atomic force microscopy (AFM) force measurements [69].

Large porous particles A new type of aerosol formulation is large porous hollow particles (LPP). Unwarranted particle aggregation in an inhaler, deposition in the mouth and throat, and rapid particle elimination from the lungs by phagocytic clearance mechanisms can lead to an inefficient therapeutic effect, for local and systemic pulmonary drug delivery [70]. LPPs have mean diameters >5 mm and mass densities <0.1 g/cm3 [71]. Although these particles have large geometric diameters, because of their low density they exhibit aerodynamic diameters comparable to smaller particles having higher densities [72,73]. These characteristics could be ideal for pulmonary drug delivery because of their low density and large surface area, which causes excellent dispersibility [74]. Furthermore, large geometric

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size can reduce clearance of this type of particle by macrophage action, thereby improving the bioavailability of inhaled pharmaceuticals [75]. The introduction of LPPs for pulmonary drug delivery was initiated by Edwards et al. [71] by encapsulation of insulin into poly lactide-co-glycolide (PLGA) microparticles. Since then, different active pharmaceutical ingredients were loaded into large porous polymeric microparticles and were used for inhalation purposes [76–81]. The same research group then tried to prepare drug itself in the form of LPP [73,82]. After that, several attempts were done to prepare drug as LPP mostly by spray drying to avoid imposing extra excipients and polymers on the lung [83–86]. To show the ability of large porous aerosols to increase systemic bioavailability as well as to provide sustained-release capability in the lungs, Edwards et al. encapsulated insulin into a biodegradable polymer and indicated the better inhalation performance and controlled-release capability of these particles in the lung [71]. Ungaro et al. confirmed the same observations with delivery of insulin into rat lung by preparation of PLGA LPP with the aid of cyclodextrins [79]. These particles can be prepared using polymeric or nonpolymeric excipients, by solvent evaporation and spraydrying techniques [66,67,75,87]. PulmoSpheresTM provide an example that is made of phosphatidylcholine, the primary component of human lung surfactant [74]. PulmoSphereTM technology, developed by Inhale Therapeutic Systems (San Carlos, CA) and now owned by Novartis (Basel, Switzerland), is based on engineering drug-containing hollow-porous microspheres by proprietary spray-drying for application in pMDIs and DPIs [87]. PulmoSphereTM formulations including ciprofloxacin [88] and tobramycin [89–92] to treat chronic Pseudomonas aeruginosa infections in cystic fibrosis patients and amphotericin B to treat invasive pulmonary aspergillosis in immunocompromised patients [93] are under active investigational new drug applications in Phase II clinical development or later. A Phase I, randomized, single-blind, placebo-controlled, dose-escalation study in patients with cystic fibrosis, chronic P. aeruginosa colonization and stable pulmonary status was investigated to evaluate tolerability and pharmacokinetic properties of DPI formulation of ciprofloxacin. The result showed ciprofloxacin DPI was well tolerated with lung function, low systemic exposure and no apparent accumulation at steady state [94]. Ciprofloxacin has also demonstrated effective deposition via PulmonSphereTM in healthy males with minimal systemic exposure [88]. Radio-labeled tobramycin PulmoSphereTM with highly dispersible porous particles and high drug loading (90%, w/w) was prepared and investigated in 14 healthy volunteers [90]. PulmoSphereTM formulation showed ninefold more efficient pulmonary drug deposition than nebulized tobramycin over a 15 min administration period. Correspondingly, serum AUC and Cmax of PulmoSphereTM tobramycin were twice than those of inhaled nebulized tobramycin. Ben-Jebria et al. prepared LPPs composed of albuterol sulfate (4%), a short-acting bronchodilator, with human serum albumin (18%), DPPC (60%) and lactose (18%) via a spray-drying method. A significant increase in inhalation capacity (more than three times) of carbacholinduced bronchoconstriction guinea pigs was achieved by inhalation of albuterol LPPs versus small nonporous albuterol particles. The long-lasting action of PulmoSphereTM was attributed to the slower clerance by phagocytosis [82]. PulmoSphereTM also showed propitious in the delivery of biologicals such as antibodies,

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peptides, proteins and mucosal vaccines [95,96]. In two interesting studies, highly porous large biodegradable polymeric particles were fabricated using ammonium bicarbonate as an effervescent porogen [80,97]. Dipalmitoylphosphatidylcholine with a protein stabilizer (lactose, trehalose or mannitol) was used as a carrier for the preparation of LPP for pulmonary delivery of a model protein, albumin, by a spray-drying method [44]. The advantages of the introduced system were suitable aerosolization performance (FPF 21–41% dependent on the type of stabilizer) and the usage of lungbiocompatible excipients in the formulation. But issues involving stability of formulation and protein upon long-term storage remain to be answered.

Technosphere1 technology Technosphere1 technology is a versatile drug delivery platform that captures and stabilizes peptides in small particles for pulmonary administration. Technosphere1 is made up of a well-characterized small organic molecule, fumaryl diketopiperazine, in a mild acid environment with a mean diameter of about (2– 5 mm), and is a suitable vehicle for pulmonary delivery for systemic absorption purposes [98]. In pulmonary administration, Technosphere1 dissolves at the neutral pH of the alveolar surface and facilitates the rapid and efficient absorption of the peptide into the systemic circulation. Unmetabolized carrier particles as ammonium salts are excreted in the urine within hours after administration. Technosphere1 formulations enable delivery of diversity of drugs with different physicochemical characteristics such as drugs ranging in molecular weight from 500 to 140,000 Da, hydrophobic and hydrophilic drugs, cationic and anionic drugs, proteins, peptides, and small molecules. Clinical pulmonary drug delivery studies using Technospheres1 intended for systemic administration of insulin, glucagons, parathyroid hormone and other drugs have indicated the reliability, efficacy and tolerability of this drug delivery system [99–101]. Afrezza1 (Technosphere1 – insulin formulation) developed by MannKind Corporation shows promising clinical data (pharmacokinetic, pharmacodynamic and safety data) regarding pulmonary delivery of insulin and recently obtained positive Phase III data for the treatment of Type 1 and Type 2 diabetes [102–104].

Regulatory status of excipients used in DPI formulations Excipients make up over 99% of the DPI product by weight, thus having a vital role in DPI formulation and are the crucial determinants of overall DPI performance. Excipients can affect drug delivery via altering drug release, bioavailability, solubility, dissolution rate, stability and even unwanted side effects of drugs [105]. One hurdle for a product to be presented to the market is the use of unapproved excipients. According to ICH guidance (ICH monographs M3, S3A and S7A) new potential excipients must be evaluated for pharmacological activity using a series of standard tests to determine its safety for human pharmaceutical usage. Achieving complete safety data of toxicological evaluation, in vivo assessment of nonclinical and clinical safety is a key factor for regulatory approval for a new excipient. Therefore, it is a necessity to perform acute and chronic toxicology studies in a rodent species and a mammalian non-rodent species by the route of administration intended for clinical application. Consequently, although 6

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most of the introduced carriers are endogen materials and even used as cell nutrition elements in cell culture studies, in vivo investigations addressing the compensation of lung in chronic exposure should be carried out. In addition to carrier nature, its physicochemical properties such as size, morphology and surface characteristics greatly affect the performance of the formulation that should be considered in excipient selection for DPI formulation [49,106,107]. Other aspects such as reproducibility, batch uniformity and powder flow are crucial factors that should be considered for carrier selection. The importance of flow properties of powders (drug and carriers) in device emptying rate and consequently improving the drug-lung deposition and enhancing its pharmacological effect have been demonstrated [108–110]. Therefore, powder flow has been introduced as a key predictor of in vitro and in vivo DPI performance [10]. Content uniformity is the main challenge in DPI formulation. DPIs must meet specific standards for the average drug content of the emitted dose and dose uniformity. For example, FDA draft guidance states that 90% of inhalers tested must deliver active drug within 80–120% of the label claim, and that all inhalers tested must deliver 75–125% of label claim [111]. A standard method is used to calculate the emitted dose from a DPI and its variability by collecting the discharge on a filter. A study result showed that some commercial DPIs did not emit a dose consistent with the stated label claim, and that the variability in emitted dose can be substantial [112]. The dose emission through different inhaler devices, Spinhaler1, Turbuhaler1 and Diskhaler1, at different inhalation flow rates showed considerable sensitivity of dose delivery to flow rate. The Diskhaler1 was the most sensitive to low flow rates, emitting just 30% of the claimed label dose at 20 l/min [113]. These findings indicated that it can be guaranteed that the patient receives the desired dose of medication despite variations in inspiratory flow rate.

Concluding remarks Increasing prevalence of pulmonary diseases with high mortality and morbidity such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, tuberculosis and lung cancer might raise interest in using DPI drug delivery for treatment of these pathologies. Insufficient delivery of drug to the lower airway regions is a major challenge for DPI formulations. The main goal in the inhalation field is to obtain reproducible high pulmonary deposition that can be greatly affected by physicochemical characteristics of the carrier. This could be achieved by successful carrier selection and careful process optimization. In the pharmaceutical industry, the need for safe and efficient carriers for a wide range of drugs has become greater than ever and the restriction of lactose has been a barrier to the development of new carriers. Owing to use of generally recognized as safe (GRAS) excipients in pulmonary delivery they must meet specific conditions including being endogenous, have no potential to irritate or injure the lungs and be able to be metabolized or cleared. Carriers such as mannitol, trehalose, erythritol, sorbitol, raffinose, xylitol, dextrose, maltitol and maltose are potential alternative carriers to lactose in DPIs. The application of introduced carriers is summarized in Table 1. Among them, mannitol might be the more promising carrier for fabrication of DPI formulation. Mannitol is the most abundant polyol in nature, inert with an established toxicity profile,

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TABLE 1

Application of alternative carriers in dry powder inhaler formulations Carrier

Drug

Outcome

Refs

Mannitol

Insulin

Better inhalation performance of microcapsules compared with sorbitol and microcapsules alone Mannitol showed the highest inhalation performance among glucose, sorbitol, maltitol and xylitol Crystallized mannitol produced higher fine-particle dose than lactose and maltitol

[10]

Terbutaline sulfate or formoterol fumarate Ciprofloxacin Salbutamol sulfate Salbutamol sulfate and budesonide Salbutamol sulfate Salbutamol sulfate Salbutamol sulfate Salbutamol sulfate Meloxicam Trehalose

Albuterol, ipratropium Lysozyme (as a model protein)

Erythritol

Glucagon Salbutamol sulfate

Co-spray-dried mannitol and ciprofloxacin formed a DPI formulation with enhanced therapeutic efficiency Acetone and ethanol crystallized mannitol showed superiority in drug aerosolization to commercial lactose and mannitol The highest respirable fraction of drugs was achieved for mannitol among other carriers (lactose and glucose) Recrystallized mannitol particles from the various ratio of ethanol:water improved the aerosolization efficiency of drug compared with commercial mannitol Freeze-dried mannitol demonstrated superior DPI performance in comparison with spray-dried mannitol and commercial mannitol. Crystallized mannitol alone and in combination with lactose showed enhanced DPI performance of drug compared with commercial lactose and mannitol Composite mannitol improved drug aerosolization efficiency compared with regular mannitol Suitable inhalation performance of mannitol-based microcomposites compared with mannitol alone

[29] [30] [34] [36] [37] [38] [39] [41] [42] [43]

Highest respirable fraction of both drugs among other carriers (mannitol and lactose) Prepared nanoporous/nanoparticulate microparticles of trehalose and raffinose showed excellent potential for peptide or protein delivery to the lung

[49]

Better drug aerosolization than lactose as proved by in vitro and in vivo experiments Lower inhalation performance of drug compared with lactose

[55]

[66]

[57]

Sorbitol

Interferon-b Salbutamol sulfate Salbutamol sulfate

Improved stability of interferon-b in jet-milling process Comparable inhalation outcome with lactose and mannitol Sorbitol, maltose and dextrose failed to increase drug aerosolization performance compared with lactose

[62] [63] [67]

Dipalmitoylphosphatidylcholine

Albumin (as a model protein) Albuterol, estradiol and insulin

Protein and stabilizer are embedded in low-density porous matrix–up to 41% fineparticle fraction (FPF) of protein was achieved Formulated large porous hollow particles (LPPs) showed emitted doses as high as 96% and respirable fractions up to 49%

[44]

Deslorelin

Preparation of large porous PLGA particles potential for sustained delivery of proteins via the respiratory tract Efficient pulmonary delivery of bioactive protein by large porous particles confirmed by in vivo study Highly porous large polymeric microparticles with favorable aerodynamic properties and ability for sustained local drug delivery by inhalation

[72]

Poly(lactic-co-glycolic acid) (PLGA)

Insulin Lysozyme (as a model protein) and doxorubicin

less hygroscopic than lactose and does not have a reducing effect. Owing to its biological stabilizing efficiency properties, mannitol has been used broadly in commercial pharmaceutical protein formulations. The focus of researchers on mannitol, recently publishing a few articles on its properties and characteristics in DPIs in several dimensions, will pave the way for its future widespread application in formulation of DPIs. Technologies for engineering

[73]

[79] [80]

carrier particle shape, density and size will continue to develop to enhance the effectiveness of pulmonary drug formulations. This approach could enable more drugs to be delivered through this route for local treatment of lung diseases or systemic therapy.

Conflicts of interest The authors declare no conflicts of interest.

References 1 Kaialy, W. et al. (2011) The influence of physical properties and morphology of crystallised lactose on delivery of salbutamol sulphate from dry powder inhalers. Colloids Surf. B: Biointerfaces 89, 29–39 2 Kaialy, W. and Nokhodchi, A. (2012) Antisolvent crystallisation is a potential technique to prepare engineered lactose with promising aerosolisation properties: effect of saturation degree. Int. J. Pharm. 437, 57–69

3 Kaialy, W. et al. (2011) Characterisation and deposition studies of recrystallised lactose from binary mixtures of ethanol/butanol for improved drug delivery from dry powder inhalers. AAPS J. 13, 30–43 4 Kaialy, W. et al. (2011) Dry powder inhalers: mechanistic evaluation of lactose formulations containing salbutamol sulphate. Int. J. Pharm. 423, 184–194

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5 Kaialy, W. et al. (2011) Improved aerosolization performance of salbutamol sulfate formulated with lactose crystallized from binary mixtures of ethanol—acetone. J. Pharm. Sci. 100, 2665–2684 6 Patton, J.S. and Platz, R.M. (1992) Pulmonary delivery of peptides and proteins for systemic action. Adv. Drug Deliv. Rev. 8, 179–228 7 Rahimpour, Y. and Hamishehkar, H. (2012) Lactose engineering for better performance in dry powder inhalers. Adv. Pharm. Bull. 2, 183–187 8 European Commission-Health & Consumer Protection Directorate, (2002) Provisional statement on the safety of calf-derived rennet for the manufacture of pharmaceutical grade lactose. Available at: http://ec.europa.eu/food/fs/sc/ssc/ out255_en.pdf 9 Glasnapp, A. (1998) Alternatives for the lactose-intolerant patient. Int. J. Pharm. Compd. 2, 412–413 10 Hamishehkar, H. et al. (2010) Effect of carrier morphology and surface characteristics on the development of respirable PLGA microcapsules for sustained-release pulmonary delivery of insulin. Int. J. Pharm. 389, 74–85 11 Hamishehkar, H. et al. (2010) Pharmacokinetics and pharmacodynamics of controlled release insulin loaded PLGA microcapsules using dry powder inhaler in diabetic rats. Biopharm. Drug. Dispos. 31, 189–201 12 Todo, H. et al. (2001) Effect of additives on insulin absorption from intratracheally administered dry powders in rats. Int. J. Pharm. 220, 101–110 13 Carpenter, J.F. et al. (1997) Rational design of stable lyophilized protein formulations: some practical advice. Pharm. Res. 14, 969–975 14 Prime, D. et al. (1997) Review of dry powder inhalers. Adv. Drug Deliv. Rev. 26, 51–58 15 Hamishehkar, H. et al. (2010) Influence of carrier particle size, carrier ratio and addition of fine ternary particles on the dry powder inhalation performance of insulin-loaded PLGA microcapsules. Powder Technol. 201, 289–295 16 Iida, K. et al. (2003) Effect of surface covering of lactose carrier particles on dry powder inhalation properties of salbutamol sulfate. Chem. Pharm. Bull. 51, 1455–1457 17 Schiavone, H. et al. (2004) Evaluation of SCF-engineered particle-based lactose blends in passive dry powder inhalers. Int. J. Pharm. 281, 55–66 18 Sebti, T. and Amighi, K. (2006) Preparation and in vitro evaluation of lipidic carriers and fillers for inhalation. Eur. J. Pharm. Biopharm. 63, 51–58 19 Pilcer, G. et al. (2012) Lactose characteristics and the generation of the aerosol. Adv. Drug Deliv. Rev. 64, 233–256 20 Traini, D. and Young, P.M. (2013) Formulation of inhalation medicines. In In Inhalation Drug Delivery: Techniques and Products (Colombo, P. et al. eds), pp. 31–45, John Wiley & Sons 21 Telko, M.J. and Hickey, A.J. (2005) Dry powder inhaler formulation. Resp. Care 50, 1209–1227 22 Cegla, U.H. (2004) Pressure and inspiratory flow characteristics of dry powder inhalers. Respir. Med. 98, S22–S28 23 Dunbar, C.A. et al. (2000) A comparison of dry powder inhaler dose delivery characteristics using a power criterion. PDA. J. Pharm. Sci. Technol. 54, 478–484 24 Malcolmson, R.J. and Embleton, J.K. (1998) Dry powder formulations for pulmonary delivery. Pharm. Sci. Technol. Today 1, 394–398 25 Zeng, X.M. et al. (2000) The influence of carrier morphology on drug delivery by dry powder inhalers. Int. J. Pharm. 200, 93–106 26 Zeng, X.M. et al. (2000) The influence of lactose carrier on the content homogeneity and dispersibility of beclomethasone dipropionate from dry powder aerosols. Int. J. Pharm. 197, 41–52 27 Momin, M.-N. et al. (2011) Investigation into alternative sugars as potential carriers for dry powder formulation of budesonide. BioImpacts 1, 105–111 28 Hamishehkar, H. et al. (2012) The role of carrier in dry powder inhaler. In Recent Advances in Novel Drug Carrier Systems (Sezer, A.D., ed.), pp. 39–66, InTech 29 Steckel, H. and Bolzen, N. (2004) Alternative sugars as potential carriers for dry powder inhalations. Int. J. Pharm. 270, 297–306 30 Saint-Lorant, G. et al. (2007) Influence of carrier on the performance of dry powder inhalers. Int. J. Pharm. 334, 85–91 31 Kaialy, W. et al. (2010) The enhanced aerosol performance of salbutamol from dry powders containing engineered mannitol as excipient. Int. J. Pharm. 392, 178–188 32 Mansour, H.M. et al. (2010) Dry powder aerosols generated by standardized entrainment tubes from alternative sugar blends: 3. Trehalose dihydrate and Dmannitol carriers. J. Pharm. Sci. 99, 3430–3441 33 Tang, P. et al. (2009) Characterisation and aerosolisation of mannitol particles produced via confined liquid impinging jets. Int. J. Pharm. 367, 51–57 34 Adi, H. et al. (2010) Co-spray-dried mannitol-ciprofloxacin dry powder inhaler formulation for cystic fibrosis and chronic obstructive pulmonary disease. Eur. J. Pharm. Sci. 40, 239–247

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35 Littringer, E.M. et al. (2012) Spray dried mannitol carrier particles with tailored surface properties – the influence of carrier surface roughness and shape. Eur. J. Pharm. Biopharm. 82, 194–204 36 Kaialy, W. et al. (2011) Effect of carrier particle shape on dry powder inhaler performance. Int. J. Pharm. 421, 12–23 37 Harjunen, P. et al. (2003) Effects of carriers and storage of formulation on the lung deposition of a hydrophobic and hydrophilic drug from a DPI. Int. J. Pharm. 263, 151–163 38 Kaialy, W. et al. (2010) Engineered mannitol as an alternative carrier to enhance deep lung penetration of salbutamol sulphate from dry powder inhaler. Colloids Surf. B: Biointerfaces 79, 345–356 39 Kaialy, W. and Nokhodchi, A. (2013) Freeze-dried mannitol for superior pulmonary drug delivery via dry powder inhaler. Pharm. Res. 30, 458–477 40 Kaialy, W. and Nokhodchi, A. (2013) Treating mannitol in a saturated solution of mannitol: a novel approach to modify mannitol crystals for improved drug delivery to the lungs. Int. J. Pharm. 448, 58–70 41 Kaialy, W. et al. (2012) The effect of engineered mannitol-lactose mixture on dry powder inhaler performance. Pharm. Res. 29, 2139–2156 42 Young, P.M. et al. (2008) Composite carriers improve the aerosolisation efficiency of drugs for respiratory delivery. J. Aerosol. Sci. 39, 82–93 43 Poma´zi, A. et al. (2013) Effect of polymers for aerolisation properties of mannitol based microcomposites containing meloxicam. Eur. Polym. J. 49, 2518–2527 44 Bosquillon, C. et al. (2004) Aerosolization properties, surface composition and physical state of spray-dried protein powders. J. Control. Release 99, 357–367 ¨ le, S. et al. (2008) Stabilization of IgG1 in spray-dried powders for inhalation. 45 Schu Eur. J. Pharm. Biopharm. 69, 793 ¨ le, S. et al. (2007) Conformational analysis of protein secondary structure 46 Schu during spray-drying of antibody/mannitol formulations. Eur. J. Pharm. Biopharm. 65, 1–9 47 Hulse, W.L. et al. (2008) Do co-spray dried excipients offer better lysozyme stabilisation than single excipients? Eur. J. Pharm. Sci. 33, 294–305 48 Ong, H.X. et al. (2013) The effects of mannitol on the transport of ciprofloxacin across respiratory epithelia. Mol. Pharmaceut. 10, 2915–2924 49 Cline, D. and Dalby, R. (2002) Predicting the quality of powders for inhalation from surface energy and area. Pharm. Res. 19, 1274–1277 50 Li, X. and Mansour, H.M. (2011) Physicochemical characterization and water vapor sorption of organic solution advanced spray-dried inhalable trehalose microparticles and nanoparticles for targeted dry powder pulmonary inhalation delivery. AAPS PharmSciTech 12, 1420–1430 51 Sou, T. et al. (2013) The effect of amino acid excipients on morphology and solidstate properties of multi-component spray-dried formulations for pulmonary delivery of biomacromolecules. Eur. J. Pharm. Biopharm. 83, 234–243 52 Lopes, J.A.J. et al. (2010) Erythritol: crystal growth from the melt. Int. J. Pharm. 388, 129–135 53 Cohen, S. et al. (1993) Water sorption, binding and solubility of polyols. J. Chem. Soc., Faraday Trans. 89, 3271–3275 54 Munro, I.C. et al. (1998) Erythritol: an interpretive summary of biochemical, metabolic, toxicological and clinical data. Food Chem. Toxicol. 36, 1139–1174 55 Endo, K. et al. (2005) Erythritol-based dry powder of glucagon for pulmonary administration. Int. J. Pharm. 290, 63–71 56 Gonnissen, Y. et al. (2007) Development of directly compressible powders via cospray drying. Eur. J. Pharm. Biopharm. 67, 220–226 57 Traini, D. et al. (2006) Comparative study of erythritol and lactose monohydrate as carriers for inhalation: atomic force microscopy and in vitro correlation. Eur. J. Pharm. Sci. 27, 243–251 58 Li, S. et al. (1996) Effects of reducing sugars on the chemical stability of human relaxin in the lyophilized state. J. Pharm. Sci. 85, 873–877 59 Dubost, D.C. et al. (1996) Characterization of a solid state reaction product from a lyophilized formulation of a cyclic heptapeptide: a novel example of an excipientinduced oxidation. Pharm. Res. 13, 1811–1814 60 Cryan, S.A. (2005) Carrier-based strategies for targeting protein and peptide drugs to the lungs. AAPS J. 7, 20–41 61 Platz, R. et al. (1991) Pharmaceutical aerosol formulation of solid polypeptide microparticles and method for the preparation thereof. In World Patent 9116038. 62 Platz, R. et al. (1994) Process for preparing micronized polypeptide drugs. In US Patent 5354562. 63 Tee, S.K. et al. (2000) The use of different sugars as fine and coarse carriers for aerosolised salbutamol sulphate. Int. J. Pharm. 208, 111–123 64 Hassan, M.S. and Lau, R. (2010) Feasibility study of pollen-shape drug carriers in dry powder inhalation. J. Pharm. Sci. 99, 1309–1321 65 Pilcer, G. and Amighi, K. (2010) Formulation strategy and use of excipients in pulmonary drug delivery. Int. J. Pharm. 392, 1–19

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´ ga´in, O.N. et al. (2011) Particle engineering of materials for oral inhalation by dry 66 O powder inhalers. I. Particles of sugar excipients (trehalose and raffinose) for protein delivery. Int. J. Pharm. 405, 23–35 67 Zeng, X.M. et al. (2007) Humidity-induced changes of the aerodynamic properties of dry powder aerosol formulations containing different carriers. Int. J. Pharm. 333, 45–55 68 Young, P.M. et al. (2007) Influence of humidity on the electrostatic charge and aerosol performance of dry powder inhaler carrier based systems. Pharm. Res. 24, 963–970 69 Hooton, J.C. et al. (2006) Predicting the behavior of novel sugar carriers for dry powder inhaler formulations via the use of a cohesive–adhesive force balance approach. J. Pharm. Sci. 95, 1288–1297 70 Suraj, D. et al. (2012) Pulmonary drug delivery using large, porous-hollow inhaled particles. Int. J. Nat. Product Sci. 1, 35 71 Edwards, D.A. et al. (1997) Large porous particles for pulmonary drug delivery. Science 276, 1868–1871 72 Koushik, K. and Kompella, U.B. (2004) Preparation of large porous deslorelin– PLGA microparticles with reduced residual solvent and cellular uptake using a supercritical carbon dioxide process. Pharm. Res. 21, 524–535 73 Vanbever, R. et al. (1999) Formulation and physical characterization of large porous particles for inhalation. Pharm. Res. 16, 1735–1742 74 Labiris, N.R. and Dolovich, M.B. (2003) Pulmonary drug delivery. Part II: the role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications. Br. J. Clin. Pharmacol. 56, 600–612 75 Musante, C.J. et al. (2002) Factors affecting the deposition of inhaled porous drug particles. J. Pharm. Sci. 91, 1590–1600 76 Dhanda, D.S. et al. (2013) Supercritical fluid technology based large porous celecoxib–PLGA microparticles do not induce pulmonary fibrosis and sustain drug delivery and efficacy for several weeks following a single dose. J. Control. Release 168, 239–250 77 Gupta, V. et al. (2013) Inhaled PLGA particles of prostaglandin E1 ameliorate symptoms and progression of pulmonary hypertension at a reduced dosing frequency. Mol. Pharm. 10, 1655–1667 78 Patel, B. et al. (2012) PEG-PLGA based large porous particles for pulmonary delivery of a highly soluble drug, low molecular weight heparin. J. Control. Release 162, 310–320 79 Ungaro, F. et al. (2009) Insulin-loaded PLGA/cyclodextrin large porous particles with improved aerosolization properties: in vivo deposition and hypoglycaemic activity after delivery to rat lungs. J. Control. Release 135, 25–34 80 Yang, Y. et al. (2009) Development of highly porous large PLGA microparticles for pulmonary drug delivery. Biomaterials 30, 1947–1953 81 Rawat, A. et al. (2008) Inhalable large porous microspheres of low molecular weight hepar in vitro in vivo evaluation. J. Control. Release 128, 224–232 82 Ben-Jebria, A. et al. (1999) Large porous particles for sustained protection from carbachol-induced bronchoconstriction in guinea pigs. Pharm. Res. 16, 555–561 83 Pham, D.-D. et al. (2013) Formulation of pyrazinamide-loaded large porous particles for the pulmonary route: avoiding crystal growth using excipients. Int. J. Pharm. 454, 668–677 84 Garcia-Contreras, L. et al. (2007) Inhaled large porous particles of capreomycin for treatment of tuberculosis in a guinea pig model. Antimicrob. Agents Chemother. 51, 2830–2836 85 Steckel, H. and Brandes, H.G. (2004) A novel spray-drying technique to produce low density particles for pulmonary delivery. Int. J. Pharm. 278, 187–195 86 Tsapis, N. et al. (2003) Direct lung delivery of para-aminosalicylic acid by aerosol particles. Tuberculosis 83, 379–385 87 Watts, A.B. and Williams, R.O., 3rd (2011) Nanoparticles for pulmonary delivery. In Controlled Pulmonary Drug Delivery (Smyth, H.D.C. and Hickey, A.J., eds), pp. 335–366, Springer, New York 88 Stass, H. et al. (2008) Pharmacokinetics of ciprofloxacin PulmoSphere1 inhalational powder. J. Cyst. Fibros. 7, S26 89 Geller, D.E. et al. (2007) Novel tobramycin inhalation powder in cystic fibrosis subjects: pharmacokinetics and safety. Pediatr. Pulm. 42, 307–313

REVIEWS

90 Newhouse, M.T. et al. (2003) Inhalation of a dry powder tobramycin PulmoSphere formulation in healthy volunteers. Chest 124, 360–366 91 Konstan, M.W. et al. (2011) Tobramycin inhalation powder for P. aeruginosa infection in cystic fibrosis: the EVOLVE trial. Pediatr. Pulmonol. 46, 230–238 92 Konstan, M.W. et al. (2011) Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: the EAGER trial. J. Cyst. Fibros. 10, 54–61 93 Dellamary, L. et al. (2004) Rational design of solid aerosols for immunoglobulin delivery by modulation of aerodynamic and release characteristics. J. Control. Release 95, 489–500 94 Stass, H. et al. (2013) Tolerability and pharmacokinetic properties of ciprofloxacin dry powder for inhalation in patients with cystic fibrosis: a phase I, randomized, dose-escalation study. Clin. Ther. 35, 1571–1581 95 Bot, A.I. et al. (2000) Novel lipid-based hollow-porous microparticles as a platform for immunoglobulin delivery to the respiratory tract. Pharm. Res. 17, 275–283 96 Geller, D.E. et al. (2011) Development of an inhaled dry-powder formulation of tobramycin using PulmoSphereTM technology. J. Aerosol. Med. Pulm. Drug Deliv. 24, 175–182 97 Ungaro, F. et al. (2010) Engineering gas-foamed large porous particles for efficient local delivery of macromolecules to the lung. Eur. J. Pharm. Sci. 41, 60–70 98 Setter, S.M. et al. (2007) Inhaled dry powder insulin for the treatment of diabetes mellitus. Clin. Ther. 29, 795–813 99 Lian, H. et al. (2000) A self-complementary, self-assembling microsphere system: application for intravenous delivery of the antiepileptic and neuroprotectant compound felbamate. J. Pharm. Sci. 89, 867–875 100 Mohnike, K. et al. (2000) Continuous sc infusion with glucagon and intermittent sc treatment with octreotide in persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI). Exp. Clin. Endocrinol. Diabetes 108, S127 ¨ tzner, A. et al. (2002) TechnosphereTM/Insulin-a new approach for 101 Pfu effective delivery of human insulin via the pulmonary route. Diabetes Technol. Ther. 4, 589–594 102 Leone-Bay, A. and Grant, M. (2006) Technosphere1 technology: a platform for inhaled protein therapeutics. ONDrugDelivery 8–11 103 Phung, O.J. (2011) Technosphere insulin: an inhaled mealtime insulin for the treatment of type 1 and type 2 diabetes mellitus. Formulary 46, 14–17 104 Carroll, J. (2013) MannKind posts positive PhIII diabetes responses for inhaled insulin. Available at: http://www.fiercebiotech.com/story/mannkind-soars-after-inhaledafrezza-delivers-positive-phiii-results/2013-08-14 105 Baldrick, P. (2000) Pharmaceutical excipient development: the need for preclinical guidance. Regul. Toxicol. Pharm. 32, 210–218 106 Islam, N. et al. (2004) Effect of carrier size on the dispersion of salmeterol xinafoate from interactive mixtures. J. Pharm. Sci. 93, 1030–1038 107 Sethuraman, V.V. and Hickey, A.J. (2002) Powder properties and their influence on dry powder inhaler delivery of an antitubercular drug. AAPS PharmSciTech 3, 7–16 108 Kou, X. et al. (2012) Physico-chemical aspects of lactose for inhalation. Am. J. Drug Deliv. 64, 220–232 109 Smyth, H.D. and Hickey, A.J. (2005) Carriers in drug powder delivery: implications for inhalation system design. Am. J. Drug Deliv. 3, 117–132 110 Nakate, T. et al. (2004) Formulation development of inhalation powders for FK888 with carrier lactose using Spinhaler1 and its absorption in healthy volunteers. J. Control. Release 97, 19–29 111 FDA Guidance for Industry: Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products. FDA, CDER Available at: http://www.fda.gov/cder/guidance/ index.htmx 112 Hindle, M. and Byron, P.R. (1995) Dose emissions from marketed dry powder inhalers. Int. J. Pharm. 116, 169–177 113 De Boer, A. et al. (1996) Inhalation characteristics and their effects on in vitro drug delivery from dry powder inhalers. Part 2: effect of peak flow rate (PIFR) and inspiration time on the in vitro drug release from three different types of commercial dry powder inhalers. Int. J. Pharm. 138, 45–56

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