Freeze-Drying Commenrial Mannitol to Use as Carrier to Enhance Pulmonary Budesonide Via DPI - Literature review Example

? Dry Powder Inhaler (DPI) Formulation: Freeze-Drying Commercial Mannitol to Use as Carrier to Enhance Pulmonary Budesonide Delivery Via DPI By Student’s Name Student’s ID Number Module Title and Number Name of Professor/ Tutor Date of Submission Dry Powder Inhaler (DPI) Formulation: Freeze-Drying Commercial Mannitol to Use as Carrier to Enhance Pulmonary Budesonide Delivery Via DPI Introduction Dry powder inhalers (DPIs) are devices widely used for delivering drug formulations to treat various lung disorders including asthma and chronic obstructive pulmonary disease (COPD). “During an inhalation event, drug particles separate from excipient and deposit in the lower airways, the site of action” (Willett, 2012, p.20). However, delivery efficiency is poor, even with the use of advanced designs in dry powder inhaler devices. This lack of drug delivery efficiency is caused by difficulties in powder dispersion leading to poor lung deposition and high dose variability (Daniher and Zhu, 2008). Lactose which is used as inert excipient in dry powder inhalers (DPI), is considered a less suitable excipient for the next generation of inhalable products such as proteins and peptides, due to its incompatibility with drugs distinguished by primary amine moieties. Consequently, “using alternative excipients appears to be an attractive option for DPI formulations” (Kaialy and Nokhodchi, 2012, p.3). Therefore, in the pharmaceutical industry, there is growing interest in replacing lactose with other excipients which facilitate greater efficiency of drug delivery through inhalation. The possible carriers or excipients for dry powder inhalation formulations are few, because they are required to fulfill particular conditions such as “being endogenous, able to be metabolized or cleared, and have no potential to injure or irritate the lungs” (Kaialy and Nokhodchi, 2012, p.2). Hence, in the domain of inhaler drugs, it is possible to use only those excipients which are generally recognized as safe (GRAS). Mannitol is considered a valuable alternative because of its lack of a reducing effect, lower hygroscopic qualities, and production of a highly sweet aftertaste which helps to indicate the dose taken by the patient (Kaialy and Nokhodchi, 2012). The freeze drying technique retrieves dry product from aqeous solutions, and it is “commonly used for preparing injectable pharmaceutical products” (Kaialy and Nokhodchi, 2012, p.2). The purpose of this literature review is to investigate various elements related to dry powder inhaler (DPI) formulation properties, and the different parameters associated with the particle analysis of powder in dry powder inhaler formulation. Dry Powder Inhaler (DPI) Formulation Properties Best Drug Particle Characteristics for Dry Powder Inhaler (DPI) Formulation In dry powder inhaler formulation, one of the most important design requirements is the estimation of particle size (Daniher and Zhu, 2008; Park and Lee, 2000). Dry powder inhaler formulations are required to create an aerosol cloud of appropriately sized drug particles to avoid their deposition prior to reaching the site of their destination (Virchow, Crompton, Negro et al, 2008). Different geometric characteristics and physicochemical properties are examined by methods for determining the particle size distribution (PSD) of a formulation (Snow, Allen, Ennis et al, 1999). Flow rate of inhalation is associated with inhaler performance, and should be included in any comparative in vitro testing of DPI formulations (Pitchayajittipong, 2008). Internal resistance is an important component of every dry powder inhaler device, which determines the flow rate of inhalation achieved by a patient using the device. For successful development of DPI systems, it is essential to combine progress in two areas, device engineering and powder formulation engineering (Harris, 2007). Increasing therapeutic outcome through optimising drug delivery to the lung is important, and dependent to a large extent on aerodynamic diameter (Hinds, 1999), which is defined as “the diameter of an equivalent volume sphere of the same density with the same terminal velocity as the actual particle” (Marrs, Maynard and Sidell, 2007, p.40). Pharmaceutical powders are rarely spherical, however various characteristics of shape can delineate the variation from sphericity. The dynamic shape factor, according to Hinds (1999, p.51), is “the ratio of the resistance force experienced by the non-spherical falling particle to the resistance force of a spherical particle of the same volume”. The aerodynamic diameter can be increased by enlarging the particle size, augmenting the particle density, or reducing the dynamic shape factor. Controlling particle size is essential because it affects the critical function of particle deposition in the lung through inertial impaction, sedimentation, and diffusion. For particles to reach the lower airways, they should be in the 1-5 micron aerodynamic range. Particles greater than this usually deliver in the oral cavity or pharynx, while smaller particles may not get deposited (Zanen, Go and Lammers,1994). To determine “the relationship between drug/ lactose ratio and aerosolisation performance of conventional carrier based formulations” Young, Edge, Traini et al (2005, p.26) used the twin stage impinger. There were unambiguous differences in the fine particle fraction (FPF) and the fine particle dose (FPD), “as a function of dose or drug/ lactose ratio” (Young et al, 2005, p.32). Moreover, the likelihood of active sites on the lactose carrier surfaces was related to the effect of drug/ lactose ratio on aerosolisation performance (Young et al, 2005). Devices: Dry Powder Inhaler (DPI), Metered-Dose Inhaler (MDI) and Nebulizer Although medical treatment through inhalation has a long history, the introduction of nebulisers in the nineteenth century, initiated modern inhalation therapy. In the 1950s, the first pressurised metered dose inhaler (MDI) brought more compact treatments into practice (Willett, 2012). An MDI being pressurized, the dose is released at a high rateo f speed, leading to a possibility of premature deposition in the oropharynx, states Ganderton (1997). Additionally, the faulty use MDIs such as a poor coordination of actuation and inhalation leads to decreased asthma control (Giraud and Roche, 2002). Metered dose inhalers (MDI) depended on ozone-depleting chlorofluorocarbons (CFCs) as propellants. This led to the requirement for substituting CFCs with hydrofluoralkanes (HFAs), followed by reformulation of metered dose inhalers (Willett, 2012). MDIs were used for twenty years, prior to introducing the first dry powder inhaler (DPI) in 1970 (Ashurst, Malton, Prime et al, 2000). The three types of DPIs currently available in the market include a single-dose, multidose, and reservoir-based device (Smith and Parry-Billings, 2003). DPIs as compared to MDIs provide greater ease, stability and efficiency of treatment. “The differences between MDIs, DPIs, and nebulisers are based on the physical states of the dispersed phase and continuous medium” (Willett, 2012, p.22), each differing in modes of metering and dispersion. A study conducted by de Boer, Le Brun, van der Woude et al (2002) examined the effects of dry powder formulation for pulmonary drug delivery in the treatment for cystic fibrosis, as an alternative to nebulization. The results of using a powder formulation with colistin sulphate as model substance, indicate that “dry powder inhalation might be a suitable and highly efficient alternative for nebulization of antibiotic drugs in CF therapy” (de Boer et al, 2002, p.17). Barry and O’Callaghan (2003) and Dolovich, Ahrens, Hess, et al (2005) reviewed the clinical performance of the different types of inhalation devices. The evidence reveals that all classes of device are equal in quality of performance, and that their selection should be according to convenience, cost, patient preference, and treatment required. O’Connor (2004) observes that the MDI continues to be the most widely used device, holding about 80% of the global market share. Formulation Challenges of Dry Powders for Inhalation According to Daniher and Zhu (2008) and Willetts (2012), dry powder inhaler (DPI) formulations are generally composed of a blend of micronised active pharmaceutical ingredient (API) with aerodynamic diameter 1-5 micron to facilitate deposition in the small diameter airways and alveoli. Dry powder inhaler formulations are very cohesive, “have poor flowability, and are difficult to disperse into aerosol due to cohesion arising from van der Waals attraction” (Daniher and Zhu, 2008, p.225). Fluidization research confronts these problems of pulmonary drug delivery. Further, an important principle in the formulation of a dry powder aerosol is that the device “should enable a high fine particle fraction (FPF) of drug to be delivered to the lung whilst any carrier such as lactose, should remain in the upper airways” (Srichana, Martin and Marriott, 1998, p.73). Bridson, Robbins, Chen et al (2007) find that for the purpose of improved handling, dispersion and metering, the active ingredient is frequently mixed with an excipient carrier of a larger, mean geometric particle size of 70 microns. Willetts (2012) reiterates that a coarse excipient of 70 micron, typically –lactose monohydrate, is employed to help in the “handling, metering and dosing of the formulation” (p.2). These constituents are customarily combined in a secondary process of production such as high shear blending (HSB), which evenly distributes the cohesive drug particles in the bulk excipient, to result in a chemically homogenous formulation (Willetts, 2012). Carrier Modifications Freeze-drying of mannitol solutions is a useful method of developing dry powder aerosol formulations, based on its numerous advantages, state Kaialy and Nokhodchi (2012). These include “enhanced pulmonary drug delivery, maximal yield, simple, low cost effective, and low safety risk, since no organic solvents were used” (Kaialy and Nokhodchi, 2012, p.19). In the pharmaceutical industry, the use of freeze drying technique indicates significant progress towards preparing freeze dried carrier particles which could resolve some difficulties related to drug-carrier dry powder aerosol formulations, state Kaialy and Nokhodchi (2012). Further, a significant impediment to consistent and reproducible drug delivery for inhalation therapy is batch-to-batch variability in the carrier. This causes different batches of dry powder inhalation formulations, despite being “manufactured with identical components and specifications” (Marek, Donovan and Smyth, 2011, p.97). to reveal considerable differences in aerosol performance. The authors studied the outcomes of mild compression forces undergone by the carrier during powder manufacture and transport, on “the flowability and aerosol performance of a lactose- based dry powder inhaler formulation” (Marek et al, 2011, p.97). Dispersion studies employing a next generation impactor evaluated aerosol performance of treated and untreated lactose/ budesonide blends. The dispersion performance resulting from different forces of different magnitudes of compression, and applied prior to and after drug blending, was recorded. Performance variations occurred because of the “compression of the lactose onto the surfaces of the larger lactose particles due to mild processing pressures” (Marek et al, 2011, p.97). In an industrial scale hopper, simulations of storage and transport can produce notable variations in formulation perfornance, and it is estimated to be the cause of batch variations. The dry powder inhaler form of glucagon, a gut hormone used for regulating glucose homeostasis, was used for enhanced pharmacological effects. Onoue, Yamamoto, Kawabata et al (2009) found that the dry powder inhaler of glucagon with addition of citric acid revealed physicochemical and pharmacological characteristics that enabled its use as an alternative to injection form. Similarly, mucous clearance in the respiratory tract and treatment of local chronic infection such as cystic fibrosis and chronic obstructive pulmonary disease through combination therapy, resulted in successful outcomes. In this technique, mannitol and ciprofloxacin hydrochloride were integrated to develop a dry powder inhalation formulation (Adi, Young, Chan et al, 2010). Further, “two-piece capsules have proven to be excellent containers to hold powder formulations for DPI applications” (Richardson, 2011, p.4). The capsule functions as an excipient of the formulation itself, and different polymers are used to improve and safe-guard the formulation held inside, while interaction between the capsule and the dry powder inhaler formulation used, is further minimized (Richardson, 2011). Influence of Carrier Size and Influence of Carrier Morphology “For dry powder inhalation formulations, micronized drug powders are commonly mixed with coarse lactose carriers” (Zhu and Morton, 2012, p.275) to enable powder handling during the production and during drug delivery of powder aerosol in patients’ treatment. The effectiveness of dry powder inhaler formulations relies on the cohesion and adhesion of drug particles under stresses created in the flow environment during aerosolization. Success has been achieved to differing extents, by surface modification with appropriate additives which help to transform the interparticulate forces, thereby controlling the action of the dry powder inhalation formulation. Similarly, Donovan and Smyth (2010) revealed that the mechanism of drug detachment is dependent on the physical characteristics of the carrier particle population. Larger particle diameters show improved detachment mechanism, with surface roughness having positive impacts. “Tranilast (TL) has been clinically used for the treatment of airway inflammatory diseases” (Kawabata, Aoki, Matsui et al, 2011, p.178), despite its low solubility and systemic side effects. To resolve these problems, Kawaba et al (2011) developed an innovative respirable powder of tranilast (CSD/TL-RP) for inhalation treatment, using nanocrystal solid dispersion of TL (CSD/TL). Stability of CSD/TL-RP was examined with an emphasis on inhalation performance. There were no morphological changes in micronized particles on the surface of carrier particles before and after 6 months of storage at room temperature. The results on inhalation performance indicate that “inhalable TL formulation might be an interesting alternative to oral therapy for the treatment of asthma and other airway inflammatory diseases with sufficient dispersing stability” (Kawaba et al, 2011, p.178). The Use of Carriers Such as Lactose and Mannitol in Dry Powder Inhaler (DPI) “Most dry powder inhaler (DPI) formulations rely on lactose monohydrate as a carrier in the drug powder blends” (Steckel and Bolzen, 2004, p.297). The benefits of using lactose monohydrate include its thoroughly examined toxicity profile, its extensive availability, and its comparatively low price. Further, lactose crystals also have a “smooth surface, a regular shape and show good flowability” (Zeng, Martin, Marriott et al, 2001, p.55). Earlier studies had also demonstrated that the surface texture and the shape can be affected by the production process or the crystallisation technique used, state Zeng et al (2001). Thus, “currently, most of DPI formulations rely on lactose as a carrier in the drug powder blend” (Momin, Hedayati and Nokhodchi, 2011, p.105). On the other hand, because of the reducing sugar function of lactose making it unsuited with drugs such as budesonide, Momin et al (2011) examined alternative sugars to overcome the particular limitation, but still have the positive aspects of lactose. It was determined that “mannitol could be suitable as a carrier on the basis of its pharmaceutical performance and successful achievement of FPF” (Momin et al, 2011, p.105), while the more hygroscopic sugars such as sorbitol and xylitol demonstrated poor dispersability, resulting in lower fine particle fraction (FPF). Lactose cannot be employed for compounds such as formoterol, budesonide or peptides and proteins that mutually operate with the reducing sugar function of the lactose. Hence, the study conducted by Steckel and Bolzen (2004) assessed the potential use of alternative carriers such as mannitol, glucose, sorbitol, maltitol and xylitol in dry powder inhaler (DPI) formulations. Physico-chemical categorization was done of raw materials; while the aerosolization characteristic of the powders was tested on blends with the model drug substance budesonide. The researchers found that the difficulties encountered in the case of lactose monohydrate, “such as supplier variability, and variability between different qualities of one supplier” (Steckel and Bolzen, 2004, p.297), were similar to the problems experienced with the alternative carriers investigated. Thus, in the case of mannitol, different sources and qualities of the product resulted in significant differences in the fine particle fraction (FPF), ranging from 15 to 50%. The other carrier materials examined in the study also indicated similar results. Moreover, a significant decrease in the fine particle fraction (FPF) was caused by conditioning the raw material at different relative humidity which impacted the performance of drug/ carrier blends. Steckel and Bolzen (2004, p.297) asserted that “mannitol showed potential as a drug carrier to be used in DPIs whereas the more hygroscopic sugars only showed poor dispersability”. Mannitol, the most profusely available polyol in nature, has been extensively employed for “commercial pharmaceutical protein formulations due to its biological stabilizing efficiency properties” (Kaialy and Nokhodchi, 2012, p.2). Moreover, mannitol is the most commonly utilized bulking agent in freeze dried formulations, and is expecting approval in the future, for use as carrier for drug delivery through dry powder inhalers (DPI) (Schneid, Riegger and Gieseler, 2008). According to Takada, Nail and Yonese (2009), the reasons pertain to mannitol’s inertness, and properties such as cake supporting as well as ready crystallization during freeze drying, and its facilitation of drying conducted at higher product temperatures. Mannitol is a polyol cryoprotectant and a lyoprotectant that results in crystalline freeze dried systems, state Hottot, Nakagawa and Andrieu (2008). Kim, Akers and Nail (1998) observe that the eutectic combination of mannitol/ ice has a high melting temperature of – 1.50C. This promotes “efficient freeze drying and physical stability of freeze dried mannitol solid” (Kaialy and Nokhodchi, 2012, p.2). In spite of forty years of research, the foremost challenge for dry powder aerosol pharmaceutical dosage forms, continues to be low efficiency of drug delivery to the lower airway regions of the lungs. Particle Analysis of Powder in Dry Powder Inhaler (DPI ) Formulation Scanning Electron Microscopy Scanning electron microscopy (SEM) is an important method for examining particle morphology, providing “high magnification, high resolution images of particles” (Telko, 2009, p.25). Its drawback is that only a small portion of particles can be screened. Drug and carrier morphology has a vital role in drug delivery in dry powder formulations. Particle morphology can influence formulation performance, hence scanning electron microscopy (SEM) is used to characterize it (Adi, Traini, Chan et al (2008). Electrons instead of light waves, produce magnified images through scanning electron microscopy (Brittain, Bogdanowich, Bugay et al, 1991). Due to the considerable electrical energy released, “analysis is carried out in a vacuum and samples must be conductive” (Pitchayajittipong, 2008, p.44). Gold, a conducting material, is used for coating the non-conducting samples (Pitchayajittipong, 2008). High Performance Liquid Chromatography (HPLC) Assessment of Drug Content High performance liquid chromatography (HPLC) is used to determine drug concentrations, from “duplicate injections by comparison of peak area with reference peaks from external standard solutions of known concentration” (Pitchayachittipong, 2008, p.102). The results of study 1 and 2 demonstrated that the relationship between drug concentration and peak area for each drug was linear, “with linear regression analysis yielding a coefficient of determination (R2) of 1.0” (Pitchayajittipong, 2008, p.102) in the two studies undertaken. ‘In Vitro’ Multi Stage Liquid Impinger (MSLI) Characterisation of Drug Deposition For sizing aerosols, cascade impactors (Cis) including multistage liquid impingers, are the most commonly used instruments, and are recommended in both U.S. and Europe pharmacopeias. Their usefulness is based on the fact that “they measure aerodynamic size rather than equivalent volume diameter, based on cross-sectional area, like other methods” (Telko, 2009, p.22). Thus, in studying the functionality and in vitro formulation performance of crystallisation by sonication (SAX) engineered budesonide particles, is employed the multi-stage liquid impinger (MSLI) “that collects particles impinging onto liquid interfaces” (Pitchayajittipong, 2008, p.100). The MSLI has five liquid impinging stages, “and the cut-off diameters at a flow rate of 60 L.min of stages 1, 2, 3 and 4 are 13, 6.8, 3.1 and 1,7 microns respectively” (Pitchayajittipong, 2008, p.100). Further, stage 5 consists of an integral paper filter to “capture the remaining fraction of particle less than 1.7 microns” (Pitchayajittipong, 2008, p.100). For each stage of the cascade impactor, a particular cut-off diameter is associated with it, which differs with airflow. Hence the cascade impactor is required to be calibrated for different flowrates. “This airflow dependence allows investigation of the effect of different inspiratory flowrates on deposition” (Telko, 2009, p.22). Marked differences were found in the in vitro deposition of both salmeterol xinafoate (SX) and fluticasone propionate (FP), “aerosolized from single-active and combination formulations when aerosolised using the Aerolizer, rather than the Accuhaler” (Taki, Ahmed, Marriott, 2011, p.234). The production of smaller mass median aerodynamic diameter (MMAD) and larger fine particle fraction (FPF) values by the Aerolizer as compared to the Accuhaler for both SX and FP, was indicated in all products tested by Taki et al (2011). Emission of smaller doses from the Aerolizer than the Accuhaler was because of the “retention of some of the powders in the capsules used in the Aerolizer” (Taki et al, 2011, p.234). Particle Size Analysis Sieves assuming a cuboidal particle shape “retain particles whose second largest dimension exceeds the size of the sieve opening” (Telko, 2009, p.59). Taking into consideration that the excipient particles are of different and at times non-uniform shape, “the mean volumetric or aerodynamic particle size of a sieve fraction is not necessarily confined to the size of the sieves used” (Telko, 2009, p.59). A method of dispersed sizing provides mean volumetric particle sizes. It is also likely to provide the same type of turbulent conditions that separate particles. Thus, determination of the presence of fines is enabled, “which can deposit on the stages of the ELPI” (Telko, 2009, p.59) or electrical low pressure impactor. A microscopic technique validates the experiments and provides a visual evaluation of the surface morphology of particles. The principle of particles in the path of light causing light to scatter, forms the basis for particle size analysis by laser diffraction (Shekunov, Chattopadhyay, Tong et al, 2007). According to Bosquillon, Lombry, Preat et al (2001), with smaller particles, the scattering light shows larger angles. The pattern and intensity of the scattered light is detected by directing a beam of coherent, monochromatic laser light at the particles to be sized. “When a sample with a polydisperse particle size distribution is analysed, the resultant scattering pattern is achieved by integration of the scattering patterns of the particles” (Pitchayajittipong, 2008, p.47). Shekunov et al (2007) observe that by applying one of numerous mathematical theories explaining the scattering of light by particles, and the comparison of experimental and theoretical diffractograms, this pattern can then be utilized to develop a volume-weighted distribution of volume equivalent diameters (Shekunov et al, 2007). Thermal Analysis of Powders Using Differential Scanning Calorimetry (DSC) The identification of polymorphs and the presence of amorphous material in pharmaceutical solids is carried out by the technique of differential scanning calorimetry (DSC) (Telko, 2009). According to Boshhiha (2010, p.52), “differential scanning calorimetry is one of the standard techniques for the determination of crystallinity”. The differential scanning thermogrms show almost similar thermal behaviour, that is, “there is no exothermic peak which indicates amorphous content” (Boshhiha, 2010, p.52). The amorphous parts identified by water vapour sorption of the micronized salbutamol sulphate do not demonstrate glass transition. Buckton and Darcy (1999) correlate this to the detection limit of this technique, which is between 5% to 10% of amorphous content. In the Differential Scanning Calorimetry (DSC) thermograms, that of micronised fluticasone propionate (FP) indicated an endothermic peak at 2920C, “related to the melting temperature of FP” (Pitchayajittipong, 2008, p.138). The thermogram of salmeterol xinafoate (SX) revealed two endothermic peaks at 1240C and 1390C, and an exothermic peak at 1300C (Shekunov et al, 2001). The data reveals that both fluticasone propionate (FP) and salmeterol xinafoate (SX) “were present in the combined FP/SX particles, and the SAX process did not change the polymorphic form of two active ingredients” (Pitchayajittipong, 2008, p.138). Conclusion This paper has reviewed the various aspects related to dry powder inhaler (DPI) formulation properties, as well as those of the particle analysis of powder in dry powder inhaler formulation. The use of lactose continues to be popular, however, because of its reducing sugar functions, it cannot be used in pulmonary Budesonide delivery. The evidence indicates that the use of mannitol as carrier for drug delivery in dry powder inhalers, is widely supported by researchers. It was found that as compared to the use of spray dried mannitol or commercial mannitol, best outcomes in dry powder inhaler (DPI) performance is achieved by generating aerodynamically light mannitol particles from freeze drying under controlled conditions. Freeze dried mannitol powders in almost crystalline form, demonstrated enhanced aerosolization action of salbutamol sulphate from dry powder inhaler formulations (Kaialy and Nokhodchi, 2012). The various properties essential for optimal dry powder inhaler formulation were examined; and particle analysis of powder in the formulation including various tests were outlined. Bibliography Adi, H., Traini, D., Chan, H.K. and Young, P.M. (2008). The influence of drug morphology on the aerosolisation efficiency of dry powder inhaler formulations. Journal of Pharmaceutical Sciences, 97, pp.2780-2788. 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