IA 2013 | Lectures

Each one of these has 2 documents linked to it: the abstract and the slide deck

Inhalation Asia is committed to open access to its conference archive, You can find PDF copies of the IA13 lectures below.

Access to this information is free of charge, but does require you to register onto our database and agree to respect the copyrights of the different authors. Please make reference to Inhalation Asia every time you make use of the material you download.

13PL1
SARS and influenza
Ivan Hung

Over the last decade, the 2003 severe acute respiratory syndrome (SARS) epidemic, the 2009 H1N1 swine flu pandemic and the latest 2013 H7N9 avian flu epidemic have reminded us of the constant threat from novel respiratory viruses. Phylogenetic analysis has indicated a high probability that SARS coronavirus originated in bats and spread to humans via animals held in wild life markets. The latest human coronavirus EMC causing SARS-like disease in the Middle East is also phylogenetically closely related to Tylonycteris-bat-coronavirus-HKU4 and Pipistrellus-bat-coronavirus-HKU5 isolated in Hong Kong. Almost simultaneously, evidence has demonstrated that the novel 2013 H7N9 avian influenza to be a new reassortant with the H7 gene from ducks of Zhejiang, N9 from Korean wild bird and 6 internal genes from H9N2 viruses from bramblings. All this evidence has highlighted the important public health issue of emerging infections jumping from wild animals into humans. Overcrowded living conditions have also facilitated the transmission of these novel viruses. Implementation of biosecurity and regulatory measures, central slaughtering and vaccination in both humans and poultry has become the best mean of preventing such outbreaks in human. In this presentation, I will review the virology, clinical presentations, laboratory diagnosis, treatment options and preventative measures for these emerging viral infections.

DOWNLOAD PRESENTATION

13PL2
Increased risk of death with tiotropium Respimat® outweighs its benefit in the treatment of COPD
Sonal Singh

Tiotropium delivered by the Respimat® inhaler is an inhaled anticholinergic used for the treatment of chronic obstructive pulmonary disease. Evidence from mechanistic studies has accumulated that inhaled anticholinergics have pro-arrhythmic and proischemic effects. Several large randomized trials, meta-analysis and observational studies have shown that Tiotropium delivered by Respimat® inhaler increases mortality among patients with chronic obstructive pulmonary disease. Most of these deaths are cardiovascular deaths. Tiotropium respimat has not received regulatory approval in the US, because of these safety concerns. Since several alternatives are now available for COPD, with similar efficacy that do not carry these negative cardiovascular effects, tiotropium Respimat® should not be used for the treatment of COPD.

DOWNLOAD PRESENTATION

13PL3
Clinical evidence relevant to the safety of tiotropium Respimat® including patient level data
Norbert Metzdorf

Recently the safety of tiotropium when inhaled from the Respimat® has been questioned following pooled analysis of a part of available data in comparison to placebo. However this analysis was conducted without access to patient level data limiting its informative value. The by far largest long-term trial in this analyis was trial 205.372, a 1-year, placebo-controlled, double-blind, randomised efficacy and safety trial of tiotropium Respimat® 5 μg daily. The trial demonstrated statistically significant differences for all pre-specified primary endpoints (exacerbations and FEV1) and nearly all secondary efficacy endpoints. However, there was an imbalance in the incidence rate of fatal adverse events.

A pooled analysis on patient level data of the marketed dose of 5 μg of the trials, which included vital status assessment of prematurely discontinued patients, showed a numerical difference for all cause mortality of RR 1.33, CI 0.93, 1.92. The higher risk for all-cause mortality appeared to be concentrated in patients with known rhythm disorders at randomization, however the causes of death did not point to a special association with arrhythmias.
In contrast, results of a pooled analysis of tiotropium Handihaler® all-cause mortality data showed a nominally significant reduction.

These results are adequately reflected in the local Spiriva® product informations: http://www.medicines.org.uk/EMC/searchresults.aspx?term=spiriva&searchtype=QuickSearch
Speculations of higher systemic exposure following tiotropium Respimat® 5 μg inhalation compared to Handihaler® 18 μg, raised to explain the mortality imbalance, are unsubstantiated. The dose in tiotropium Respimat® (5 μg once daily) has been chosen to match the efficacy and safety of the well established tiotropium Handihaler® 18μg. Three PK-studies compared the pharmacokinetics of tiotropium after inhalation from both devices: One study in European patients found 22 and 35% higher exposure (AUC0-6 and Cmax) for Respimat® 5 μg versus Handihaler® 18 μg. A second study in Japanese patients showed virtually identical plasma levels. A newly available third study with optimized procedures for PK analysis reported 24% and 19% lower exposure (AUC0-6 and Cmax) for tiotropium Respimat® 5μg versus tiotropium Handihaler® 18μg once daily. This study also demonstrated similar PK variability for the two tiotropium formulations. To conclude, available data suggest similar systemic exposure for both devices at the marketed doses and any apparent difference in safety remains unexplained and implausible.

To confirm the hypothesis of no difference between matching formulations Boehringer Ingelheim has initiated the TIOSPIR® trial in over 17,000 patients comparing once daily tiotropium Respimat® 5μg and tiotropium Handihaler® 18μg with all-cause mortality and COPD-exacerbations as co-primary endpoints. A further arm with tiotropium Respimat® 2.5 μg once daily is included in order to inform dose selection for future combination products. The trial is supervised by an independent Data-Safety-Monitoring-Board (DSMB) with access to fully unblinded data. Based on their review every four months the DSMB has up to now and in its final assessment based on ~95% of the number of fatal events used in the sample size calculation for the trial recommended to"continue as planned". TIOSPIR® is close to finalization but still blinded.

DOWNLOAD PRESENTATION

13IL1
The quality requirements and quality standards of inhalation preparations in China
Guiliang Chen

The guidelines and technical requirements of quality of Inhalation preparations in China are mainly released from two Departments: the Chinese pharmacopoeia committee and the CFDA Center for New Drug Evaluation.

The Chinese pharmacopoeia committee is responsible for the Chinese pharmacopoeia. The Chinese pharmacopoeia 2010 version is the latest version of the pharmacopoeia, in which there are two chapters concerned with the quality requirements of inhalation preparations. "IL Aerosols, Powders for Inhalation and Nebulization" list the general requirements for preparations and "Appendix XH Determination of Particle or Droplet Size Distribution of Inhalation Preparations" for chemical and physical methods. The Chinese pharmacopoeia contains 7 varieties of aerosols (5 for inhalation) and 1 powder for inhalation. The requirements of the preparation contains only one method about the content of active ingredient in an actuation for the ex-valve dose. The particle size distribution measurement method only lists glass twin-impinger methods. This presentation will introduce the ongoing development of both general requirements of preparations and particle size distribution measurements. For a case study, the process of making pharmacopoeia aerosol monographs will be introduced as an example.

This presentation will also describe "The guideline on quality control study of inhalation preparation" issued in October 2007, and will comment on the technical requirements for inhalation preparations as personal opinions.

A new drug application or generic drug application needs to be submitted to CFDA before any prescription drug can be marketed in China. Summary, Pharmaceutical, pharmacology and toxicology, and clinical studies must be described in these applications. However, requirements for the studies vary, dependent on the type of application submitted. Applicants need to know whether the drug product has been marketed previously, and whether it has been marketed in China or in another country.

For instance, salbuterol MDI, fluticasone/salmeterol powder for inhalation will be considered by CFDA to be generic drugs as there are already marketed brand products containing these drugs in China. To deal with imported products, import drug applications refer to drugs manufactured in other countries that are proposed for import and marketing in China. These drug products should usually have been approved for marketing in their country of origin. Thus, foreign pharmaceutical companies may apply to market their products as import drugs in China and most often, they would do this via a Chinese subsidiary.

DOWNLOAD PRESENTATION

13IL2
Obstructive airway diseases in India: an insight
Arvind Bhome

Since the landmark paper on Global Burden of Diseases many are aware of the increasing prevalence, morbidity and mortality due to Chronic Respiratory Diseases within the group of Non Communicable Diseases which contribute two third burden of mortality and morbidity in most parts of the world- both the developed and the emerging. India is no exception. Amongst the CRDs Obstructive Airway Diseases- Asthma and COPD constitute the lion's share in India as well; with nearly 32 to 35 million asthma subjects and 20 to 22 million COPD subjects in the world total of 300 million asthmatics and 210 million COPD subjects. What is more alarming is that there has been a growth of 25% in asthma in India and of 30% in COPD in the last decade.

Epidemiology: Malaria and TB mortality is decreasing in India but COPD mortality is increasing. The trends from the State of Maharashtra suggest that COPD has already become number one killer. Apart from mortality the two OADs contribute 55 million cases to the morbidity statistics of the country if the WHO data from 2002 -2004 is to be believed. WHO data on DALYs lost to COPD suggest India contributes 6.7 million DALYs lost out of world total of 28 million- grossly disproportionate to the 17% humanity it hosts on 2% of earth's crust. India spent perhaps 100 Billion Rs. (2Bill.USD) on Asthma and 350 billion Rs (7 Bill.USD) on COPD in 2011.

Healthcare Services: Indian government spends less than 2% of GDP on healthcare which includes salaries of healthcare providers on its pay-role. More than 2/3 healthcare expenditure comes out of patients' own pockets. Majority of the population does not have health insurance even 10 years after opening the sector to privatization. The urban-rural divide is obvious in health infrastructure; but there is also gross regional disparity.

Drugs, Devices including Inhalational Therapy: Indian Pharma sector is very vibrant and enterprising. India has perhaps the world's most diversified Inhaler market at 10% of world cost. Inhaled therapy has exploded in the last decade. Combination inhalers available in India for more than five years are only recently making their debut in EU. Triple drug combinations such as LABA+LAMA+ICS have been available for many years. Cost and availability can't be the grouse for under-treatment. Spirometry is not yet commonplace. Asthma control remains a distant dream for many patients. Quality of care for COPD is even worse than asthma in terms of under-diagnosis, under monitoring, and under- treatment.

Market Research and future trends: The impending patent cliff may see many MNC players trying to enter the populous Indian market but the price sensitivity of the Indian marketplace is going to make it difficult for any player to dominate for long - whether Indian or Multi-national. Current chaotic scenario of more than a dozen companies competing with hundreds of inhalational formulations in the Indian market may lead to either one of the best systems of healthcare or the most chaotic one. Let us hope for the best.

DOWNLOAD PRESENTATION

13IL3
Detection of potential biomarkers in airway diseases
Judith Choi Wo Mak

A biomarker is a surrogate measurement designed to characterize and quantify an underlying disease process. Obstructive airway diseases are a group of conditions distinguished by increased resistance and obstruction in the airway passages, especially during expiration, which include asthma and chronic obstructive pulmonary disease (COPD) causing extensive mortality and morbidity worldwide. Globally, 250,000 people die of asthma every year. COPD affecting 210 million people was the fifth-leading cause of death in 2002 and it is projected to be the third-leading cause of mortality by 2030 worldwide. However, the pathogenesis of asthma and COPD has been claimed to be attributable to increased systemic and local oxidative stress.

Detection of the oxidant burden and evaluation of their progression and phenotypes by oxidant biomarkers such as 8-isoprostane have proved challenging and difficult. One of the challenges is the difficulty in the selection of samples that provide scope into the specific disease entity. In contrast to blood or urine, sampling induced sputum, bronchoalveolar lavage, or exhaled breath condensate is problematic and requires standardization. Factors such as oropharyngeal contamination, dead-space gas, and expiratory flow affect sampling techniques. There is no easy way around the methodologic complexities.

The aim of this presentation is to discuss key issues in the application of biomarkers in the treatment of obstructive airway diseases. For example, airway inflammation characterized by sputum eosinophilia is associated with frequent exacerbations (clinical phenotype), whereas airway inflammation characterized by nertrophilia has relative steroid resistance (treatment response) in asthmatic subjects. Being able to distinguish clinical and treatment-response phenotypes using a relevant biomarker has the potential to improve clinical management. The results from our group demonstrating evidences for overproduction of biomarkers of systemic oxidative stress (8-isoprostane), inflammation (C-reactive protein) and tissue damage [matrix metalloproteinase (MMP)-9] in patients with asthma and COPD during acute exacerbation, which persists during remission. There is currently a need to identify new biomarkers for obstructive airway diseases, especially their differential diagnosis. However, rigorous biological and clinical validation is necessary before a biomarker can be endorsed. Advancements in proteomic technologies, such as advanced mass spectrometry, gel electrophoresis, protein arrays and bioinformatics, provide new potential for the sensitive and specific identification of biomarkers and protein profiles in obstructive airway diseases. The noninvasive nature of sampling methods also provides convenient access to repeatedly monitor the dynamic of these biomarkers with the progression and treatment. With further research, we are in a good position to define future strategies to develop diagnostic biomarkers from bench to bedside in the years to come.

DOWNLOAD PRESENTATION

13IL4
Inhalation delivery of traditional Chinese medicine for respiratory diseases: current applications and challenges
Yong-Hong Liao

Inhalation therapy of herbal medicine has been practiced for thousands of years. The earliest written document about inhalation therapy dated back to about 2000 BC when Indian used the smoke of Atropa belladonna leaves for treatment purpose in India. Ancient traditional Chinese medicine (TCM) practitioners had also used the smoke and vapours of medicinal plants for the treatment of respiratory tract diseases. Nowadays, the applications of TCM via metered dose inhalers (MDI) or nebulization have been well documented in clinical practice and inhalation therapy of more than 50 TCM formulas has been reported for the treatment of various pulmonary diseases. These studies have demonstrated that TCM inhalation therapy for respiratory diseases offers unique advantages including decreases in doses and side effects relative to the oral or other systemic routes, particularly in adverse reactions accompanied by injectables.

In the literature, MDI based TCM products are mainly utilized for the management of respiratory infections and asthma and 4 products have been approved by the State Food and Drug Administration (SFDA). Although there are no nebulized TCM formulations approved by SFDA, nebulization therapy using injectable solutions have been extensively practiced in clinical for the treatment of asthma, bronchitis, pneumonia, emphysema, respiratory infections and other lung disorders. Among these nebulized TCM formulas, Shuang-Huang-Lian (prepared from honeysuckle flower, radix scutellariae and fructus forsythia) and Yu-Xing-Cao (Houttuynia cordata) have been most extensively studied and the clinical applications have been documented in over 100 publications. These clinical data suggested that nebulization therapy could offer improved or comparable therapeutic efficacy but less side effects compared to intravenous injections of counterparts. The inhalation route may provide a viable, noninvasive and efficacious means as an alternative to injection so as to reduce side effects often accompanied by TCM injections.

In contrast to the wide applications of TCM inhalation therapy in clinical, few efforts have paid attention to formulation technologies applicable to TCM inhalation products and most of the TCM inhalation therapies seem to lack strict quality control testing, to which inhaled western pharmaceuticals are subjected during formulation development and clinical studies. TCM companies do not possess expertise in inhalation delivery, while organizations that have in-house expertise may not have experience in TCM products. A single TCM preparation generally contains various types of chemical ingredients and such chemical complexity can result in difficulties in formulation development.

Currently, TCM inhalation delivery results mainly from clinical practitioners' choice and demand, rather than the contribution of TCM pharmaceutical industry. Before such a therapy becomes acceptable by the pharmaceutical market, the TCM industry faces a number of challenges such as variable sources of herbal material, difficulties in quality control, lack of safety evaluation, short of delivery technologies, etc. Most importantly, more clinical data from high quality clinical studies are needed to fully understand the advantages and disadvantages of TCM inhalation therapy.

DOWNLOAD PRESENTATION

13IL5
Inhalation therapy in Chinese asthmatic children
Yuzhi Chen

Asthma is one of the most common chronic disorders in children. The prevalence of asthma is in a wide difference, and it has been reported to increase in many places around the world during the last decade. In China, there was a significant trend of increase (64.84%) of asthma prevalence from 1990 to 2000. During the last decade, the population of asthmatic children in Beijing urban area has increased (in 2000 and 2010, the accumulate prevalence was 2.69% and 3.68% respectively), although the current 2 years prevalence rate did not show a significant change (2.05% in 2008 and 2.55% in 2010). And this is probably related to promotion and dissemination of Global Initiative for Asthma (GINA).

In many surveys, the first episode of wheezing mainly occurred within the first 3 years of life. Due to the lack of specific diagnostic tools or biomarkers to detect infant asthma, it is difficult to diagnose asthma in young child. Long-term follow-up, consideration of extensive differential diagnosis and observation of the response to bronchodilator are essential. Furthermore, anti-inflammation therapy is important at this period because of the prevention of airway remodelling. So we may make children 5 years and younger as the key population for asthma prevention.

Treatment of childhood asthma is divided to 2 age groups, 0-4 years and 4 years above, and relievers and controllers are prescribed at the same time in both groups. For acute severe asthma in children 4 years and younger, nebulized budesonide, short-actingβ2-agonist (SABA) and ipratropium are used one to three times in one hour to get a symptomatic relief. Systematic corticosteroids are seldom used except for acute severe exacerbation. Fluticasone /budesonide (pMDI with spacer and mask) plus SABA (pMDI) PRN are used for maintenance therapy. In children above 4 years old, ICS+LABA (DPI) are recommended as maintenance therapy for moderate or severe persistent asthma. Leukotriene modifier can be chosen according to the level of disease control.

It generally takes 2 weeks to 1 month for the lung function to be back to normal for children above 4 years old, and after asthma is controlled for 3-6 months, dose of ICS can be reduced to half.

Short-time using of neubulized corticosteroid and SABA for acute exacerbation is quickly extended in China, but the promotion and application of long-term regular inhalation steroid therapy using delivery devices such as pMDI with spacer and mask/mouthpiece, or DPI (Turbuhaler/Diskus) is far from enough. Inhalation steroid therapy can control symptoms fast and reduce the use of systemic corticosteroids and SABA PRN with much fewer side effects. ICS can improve symptoms and lung function, decrease need for additional medication, and reduce rate of asthma exacerbations and asthma-induced hospital admissions in children of all ages.

DOWNLOAD PRESENTATION

13IL6
The formulation development and device designing of INAVIR® dry powder inhaler
Kazuhiro Inoue

INAVIR® is a new dry powder inhaler for the treatment of influenza A and B virus infections developed by Daiichi Sankyo Co., Ltd. The action mechanism of INAVIR® is to inhibit the neuraminidase of influenza viruses. The most distinctive feature of INAVIR® is that the treatment is complete just by single administration. Phase III clinical studies revealed that single administration of INAVIR® elicited a comparable alleviation effect of influenza symptoms to that of multiple oral administration of oseltamivir. In order to maximize this characteristic, INAVIR® was formulated as a single-use dry powder inhaler with a high degree of usability and inhalation- strength-independent performance. The powder formulation was designed as a ternary mixture of micronized API and two types of carrier lactose. The particle size and the loading ratio of the components were optimized in terms of the fine particle fraction with a prototype device, Device A. In parallel to this formulation work, the commercial device was developed based on the TwinCaps® concept which was invented by Hovione Farmaciencia SA (Portugal). Important features of the TwinCaps® are that it consists of only two plastic parts, and that it is ready for use just after sliding a part of the device. The powder is preliminary filled directly in the tray part which has small orifices. During storage, the powder container is sealed by the body parts to prevent powder leakage. In use, a pathway for air stream is generated across the powder container space just by sliding the tray part. In addition to this excellent usability, a CDF simulation and in vitro study revealed that TwinCaps® has an efficient powder dispersion mechanism.

The designing of TwinCaps® was finalized after determining the administration dose of commercial products by clinical studies, and then the appropriateness of the device switching was verified. TwinCaps® was designed to emit the API with the same fine particle dose and aerodynamic particle size distribution as those of Device A in vitro. Based on these in vitro data, PMDA approved to judge the appropriateness of the device switching by comparing the clinical efficacy in influenza patients. A PhIII study revealed that the primary endpoint (time to illness alleviation) was equivalent between the two devices. In addition, there were no additional endpoints which show inferiority of TwinCaps® to Device A. As a result, PMDA approved the device switching.

Literature information suggest that the inhalation strength varies among the patients in the range 1.4 ~ 9.2 kPa. On the other hand, the fine particle dose of INAVIR® was consistent in the range 1.2 ~ 4 kPa suggesting that INAVIR® can be used even for patients with weak inhalation strength. This was confirmed by a post-marketing surveillance conducted between Nov. 2010 and Apr. 2011. In all age groups ranged from age 2 to 94 years, more than 80 % of patients were able to carry out successful or fairly satisfactory inhalation, and more than 90% of cases were judged effective.

DOWNLOAD PRESENTATION

13IL7
Pulmonary delivery system for the treatment of TB and lung carcinoma
Kimiko Makino

The nanocomposite particles having an aerodynamic diameter of 2.5mm composed of sugar and anti cancer drug(TAS103)-loaded PLGA nanoparticles with diameter of 100 nm can reach deep in the lungs, and they are decomposed into TAS103-loaded PLGA nanoparticles in the alveoli. When the nanocomposite particles are delivered by inhalation, the much higher concentration of TAS103 was observed in the lungs than that in plasma. Also, PLGA microspheres with the diameter of 2~3mm effectively treated the TB by inhalation.

DOWNLOAD PRESENTATION

13IL8
Amphipathic peptides-mediated delivery of siRNA for antiviral therapy against influenza
Jenny KW Lam

RNA interference (RNAi) technology has emerged as a novel and potentially effective therapy against respiratory viruses. RNAi is a naturally occurring process that inhibits specific gene expression in a post-transcriptional manner, mediated by small interfering RNA (siRNA). Properly designed siRNAs have already been shown to function as potent inhibitors of viral replication. By delivering exogenous siRNAs to mammalian cells, RNAi could be induced to degrade the viral mRNAs, leading to clearance of infection.

The design of an effective antiviral siRNA sequence is laborious but is not the limiting step. Influenza viral replication could be inhibited by targeting the viral genes encoding nucleocapsid protein (NP) or components of RNA transcriptase (PA and PB1) of the viruses. Delivery is indeed the major bottleneck to siRNA therapy. siRNAs are negatively charged hydrophilic macromolecules which are susceptible to nuclease degradation with poor membrane permeability. Multifunctional delivery vectors are therefore required to serve a number of purposes (i) protect siRNA from enzymatic degradation; (ii) facilitate cellular uptake at target cells; (iii) release siRNA at the site of action in cytoplasm and initiate RNAi mechanism.

Recently our group is investigating a series of novel pH responsive amphipathic peptides containing ionizable histidine (LAH series) or diaminopropionic acid side chains (LADap series) for siRNA delivery. These peptides can form non-covalent complexes with siRNA, effectively protect siRNA from nuclease degradation, facilitate cellular uptake via endocytosis and respond to endosomal acidification by dissociating from the complexes and destabilizing endosomal membranes, resulting in the release of siRNA into cytosol. The pKa of the peptides can be manipulated to tune their functional pH response in order to afford optimal siRNA transfer with negligible toxicity and they are highly effective at delivering siRNA and mediating specific gene silencing on a wide variety of cells even in more challenging environments such as in the presence of lung surfactants. Significant reduction of viral titers (up to 8,000-fold reduction) was observed in vitro after delivering siRNA targeting influenza viral nucleocapsid protein of H1N1 (PR8) virus to the infected mammalian cells using LAH or LADap peptides. The results suggests that the amphipathic peptides are promising delivery vectors against viral infection. Further work will be focused on the formulation of the peptides/siRNA complexes into dosage form and explore its therapeutic potential in animal model.

DOWNLOAD PRESENTATION

13IL9
Dry powder aerosol delivery - Recent developments in formulation, device, and therapeutic applications
Hak-Kim Chan

Inhalation therapy using powder aerosol delivery has progressed beyond treatment for asthma and other obstructive pulmonary diseases. Respiratory infection, pulmonary arterial hypertension and diabetes are just a few commonly cited examples. To effectively deliver the inhaled treatment, both the powder formulation and device have to be optimised. Lactose-based carrier systems have been used for years but a fundamental understanding of the aerosolisation process is yet to be fully established. By modifying the grid structure (hence the flow path and impaction) of the Aerolizer, we found drug detachment from the carrier surface occurs mainly in the swirling chamber in the device. The impaction between the powder and the device mouthpiece seems to play a much less role in generating fine particles in the aerosol.

Instead of lactose blends, carrier-free systems using drug powders without an external coarse carrier are emerging for high-dose drugs, as exemplified by the delivery of mannitol (Aridol and Bronchitol) and tobramycin (TOBI). In particular, inhaled antibiotics and combination products are becoming an interest focus for chemotherapy of various respiratory infections, such as influenza and tuberculosis. Combination antibiotics have been produced using conventional or nano spray drying techniques. It is important to consider whether the antibiotics in combination will create synergy or antagonism, an aspect which may not be obvious to aerosol scientists trying to work on the formulation. Spray freeze-drying is an alternative technique useful for production of particles with controlled porosity and aerodynamic diameter. These porous particles can provide a matrix structure to embed drug nanoparticles, thus allowing the possibility of delivering various drugs within a single matrix particle. Drug administration to the intubated patients at the hospital intensive care units has been achieved by nebulisation and propellant-driven metered dose inhalers. Only recently has powder delivery become possible for the intubated patients. We have delivered mannitol powders to these patients and found the method is safe showing efficacy of improved mucus clearance from the airways.

DOWNLOAD PRESENTATION

13IL10
Clinical trial design for tuberculosis inhaled therapies in India
Amit Misra

Tuberculosis (TB) infection is first established in the lungs, and the pathogen uses alveolar macrophages as its preferred ecological niche for survival and proliferation. Pulmonary drug delivery promises to be a route of choice for therapy of pulmonary TB. Several groups, including ours are engaged in preclinical and clinical development of inhaled therapies for TB using existing drugs. Capreomycin, a second-line drug used in patients who do not respond to the first line of treatment, is under Phase I and Phase II trials in South Africa, but the results are not yet in the public domain. We have recently concluded regulatory preclinical work on inhalable microparticles containing a combination of isoniazid and rifabutin, and are in the process of evolving a clinical plan for filing an Investigational New Drug (IND) application. In brief, the preparation is safe and efficacious against experimental animal TB. The proposed intervention in humans is to investigate inhalations as adjunct therapy to standard treatment. We first intend to study non-therapeutic outcomes of dry powder inhalation (DPI) delivery in 18 healthy volunteers, establishing pharmacokinetic parameters for comparison with mice and monkeys.The maximum tolerated dose will be established. Healthy volunteers will be recruited based on a thorough medical exam, including blood biochemistry, hematology, and ECG. Six volunteers providing informed consent will be randomized to three cohorts of six each, receiving 0.25, 2.5, and 25 mg of inhalable particles as DPI per day. Stratification by gender, body weight (50-60 kg or 61-80kg), and Nat-2 genotype will thus yield 12 strata, which is conducive to a Type I error. We intend to guard against Type I errors by crossing-over the volunteers to another study in which they would receive oral doses of the same amounts of the two drugs. For a Phase II study, we are considering inclusion of three categories of patients in three distinct arms of trials. A 14-day analysis of Early Bactericidal Activity (EBA) will be the outcome measure in each arm. The first arm will comprise newly diagnosed patients, the second will be made up of patients showing failure of first-line treatment, and the third will involve persons with HIV infected with TB. With a sample size of 50 per arm, there is 80% probability of detecting a treatment difference at a two-sided 0.05 significance level, if the true difference between treatments is 0.810 times the standard deviation in EBA.

DOWNLOAD PRESENTATION

13IL11
Oxytocin as a dry powder for inhalation to promote access to a life-saving medication in developing countries
Michelle McIntosh

Postpartum haemorrhage (PPH), usually defined as the loss of >500mL of blood within 24 hours of birth, occurs in more than 10% of all births. Associated morbidity and mortality is seen almost exclusively in developing countries, where current estimates attribute between 35 - 50 % of maternal deaths to haemorrhagic events. The routine use of the active management of the third stage of labour (AMTSL), including the administration of an uterotonic within one minute of birth, significantly lowers the incidence of PPH.

The World Health Organisation (WHO), recommends the neuropeptide uterotonic, oxytocin, as the first line therapy for the prevention and treatment of PPH. However, oxytocin is currently available as a solution for injection that requires cold chain transport and storage. This presents difficulties in developing countries where (i) the supply chain, facility infrastructure and local practices are often inadequate and do not maintain product potency; (ii) there is a shortage of skilled birth attendants to safely administer injectable drugs; and (iii) many women give birth at home.

The Monash University team is developing a low-cost, heat stable dry powder delivery system suitable for oral inhaled administration of oxytocin for use in the management of postpartum haemorrhage in low-resource settings. To this end, oxytocin has been spray dried with a range of glass forming excipients, including mannitol, trehalose and polyvinylpyrrolidone and combined with leucine to create physically robust, aerosolisable, dry powder oxytocin formulations. Formulations were characterised for primary and aerodynamic particle size, , water content and using X-ray diffraction differential scanning calorimetry and thermo-gravimetric analysis. The chemical stability of oxytocin in dry powder was evaluated over 180 days at 25, 40 and 50oC and the stability of the dry powder inhalation formulations was compared to the commercial liquid formulation for injection, Syntocinon®.

Pre-clinical pharmacokinetic and pharmacodynamic evaluations of a representative formulation have been conducted in a post-partum sheep model. In a cross-over study design, sheep (n=6) received oxytocin as a 200 IU dry powder insufflation to the lungs and a 10IU intramuscular (IM) injection, with a washout period between doses exceeding five times the terminal elimination half-life of oxytocin. Immediately following each administration blood samples were collected for 30 min and electromyography data (characterising uterine contractions) was collected for 90 min.

The dry powder formulation of oxytocin is significantly more stable than the commercial solution for injection and the plasma pharmacokinetic profiles are essentially similar with a Cmax of 563.6 ± 152.6 pg/mL and Tmax of 2.3 ± 0.4 min, following pulmonary delivery and a Cmax of 511.2 ± 98.8pg/mL and Tmax of 5.0 ± 1.2min following IM injection. The onset of the first contractions after administration was 3.3 ± 0.8 and 4.2 ± 0.2 min for pulmonary and IM, respectively and the duration of the first contractions was 5.2 ± 1.6 and 4.9 ± 1.2 min for pulmonary and IM, respectively.

Studies conducted to date support the further development of a dry powder, pulmonary delivery system of oxytocin to overcome the major barriers to widespread use of oxytocin in low-resource settings. Such a product has the potential to dramatically increase access to oxytocin and facilitate the widespread implementation of the active management of the third stage of labour.

DOWNLOAD PRESENTATION

13IL12
The Chinese market for asthma and COPD inhalation products
Anny Shen

ue to the increasing population in Chinese cities, use of motor cars and rapid industrial expansion the increase in air pollution is a major cause of human respiratory diseases. Currently, according to a Chinese health official report, the number of asthma patients in 2000 was 20 million and has now increased to over 30 million and is increasing by circa. 4% per year. For children below 14 years of age, 4% suffer from asthma.

The number of cigarette smokers is now over 300 million in China and Chronic Obstructive Pulmonary Disease (COPD) is currently among the top four national causes of death. There are more than 40 million COPD patients in China and is increasing by approximately 6% per year. For people over 60 years of age, 3% suffer from COPD.

2011 sales volumes for all anti-asthma and COPD drugs: tablets, injections, inhalers was RMB 11billion and increased by over 20% per year between 2007-2011 with a 30% increase per year between 2007-2011 for inhalation products, with three international pharmaceutical companies gaining 80% of the market for inhalation products.

There are few Traditional Chinese Medicines ( TCM of MDIs) available and treatment for Asthma and respiratory diseases relies on western medicinal products.

The article will review the status of inhalers used in China: Nebuliser, DPIs and MDIs of both CFC and HFA versions and considers the future trends in inhaler usage for the treatment of Asthma and COPD in China.

DOWNLOAD PRESENTATION

13IL13
Metered dose inhalers or dry powder inhalers, a tough decision and practical considerations
Shuguang Hou

There are several factors that are driving more and more pharmaceutical companies to step into inhalation products business in China. The drug market for respiratory diseases is fast growing; the patent protection for a series of blockbuster inhalation products is expiring; and the transition from CFC to HFA metered dose inhalers is bringing new opportunities. The pharmaceutical companies are facing a difficult decision: which product, metered dose inhalers (MDIs) and dry powder inhalers (DPIs), should be selected for future development?

The MDIs and DPIs both belong to pulmonary drug delivery products, however, the devices, formulations and manufacturing process between them are totally different, thus the cost of investment is different. Market share (such as physician awareness, patient use, etc) and technical expertise also are the top considerations for a pharmaceutical company to make decisions between these two dosage forms.

There exist many uncontrollable factors which influence the success of a product development, such as availability of quality active pharmaceutical ingredients (APIs), excipients and HFA MDI components (i.e. valves, canisters and actuators). A suitable DPI device is difficult to obtain and costly. Although there are a few previously developed DPI products available in China markets, China now has strict intellectual property laws. No DPI devices have been locally developed and commercially available.

From the regulatory perspectives, the definition of a generic product for an inhaler is not clearly defined, especially for DPIs. The European Medicines Agency published guidelines on the requirements for demonstration of therapeutic equivalences between two inhaled products, however, this is not the case for USA FDA. USA FDA may have more strict requirements for the generic DPIs. The regulatory requirements in China will significantly influence the time and cost of development for generic inhalation products, especially for DPIs.

Obviously it is difficult to for a pharmaceutical company to determine the products to be developed between MDIs and DPIs. This presentation will discuss above issues in more details.

DOWNLOAD PRESENTATION

13CL3
Characterisation of HCI-H441 cells as an in vitro model of small airways epithelial barrier
Carsten Ehrhardt

The absence of a readily available, continuously growing cell line of human small airways epithelial phenotype and the ability to form polarised, electrically tight monolayers has seriously compromised inhalation drug disposition research. Therefore, we investigated if the human lung adenocarcinoma cell line, NCI-H441, has potential to serve as an in vitro model of human distal lung epithelium.

Monolayer barrier properties were studied by immunocytochemistry (ICC) against the tight junction protein, ZO-1, and measurement of transepithelial electrical resistance (TEER) over time. The expression of P-glycoprotein (P-gp) and organic cation/carnitine transporters (OCT/Ns) was investigated by ICC and Western blot. Bi-directional transport studies were performed using the P-gp substrate, rhodamine 123 (Rh123). Uptake of ASP+, [14C]-TEA and [3H]-acetylcarnitine was carried out to determine OCT/N function in vitro. Furthermore, the effects of TEA, MPP+, amantadine, verapamil, hemicholinium-3, D-carnitine and ergothioneine on organic cation uptake were studied.

NCI-H441 cells formed confluent, electrically tight monolayers with peak TEER values above 1000 Ωcm2, after 13 days in culture (Figure 1). Presence of ZO-1, P-gp, OCT1, OCT2, OCT3, OCTN1 and OCTN2 was confirmed by immunolot and ICC. The expression pattern of membrane transporters matched that of freshly isolated human alveolar epithelial cell in primary culture. Rh123 showed a net secretory transport, which was sensitive to inhibition by verapamil. The calculated Rh123 efflux ratio was 3.43 in NCI-H441 cells, which was similar to the value of 3.09 obtained in monolayers of human primary ATI-like cells. The uptake of cationic substrates was generally time and temperature-dependent. TEA, amantadine and verapamil markedly inhibited ASP+ uptake into NCI-H441 cells, whereas the effect of MPP+ was less pronounced. In the case of [14C]-TEA, verapamil and MPP+ most efficiently inhibited the uptake, whilst amantadine and HC-3 did not show an attenuating effect. D-carnitine and ergothioneine significantly attenuated [3H]-acetylcarnitine uptake into NCI-H441 cells.

NCI-H441 cells are the first cell line of human distal lung epithelial origin with the ability to form monolayers with appreciable barrier properties. TEER values of NCI-H441 monolayers were consistent with what is commonly reported for monolayers of human ATI-like cells in primary culture. P-gp activity was also comparable to that of human ATI-like monolayers, however significantly lower than data published on Caco-2 cells. Consequently, the NCI-H441 cell line is a promising model to study drug disposition in the small airways in vitro.

DOWNLOAD PRESENTATION

13CL2
Defining DPI in vitro BE for the US market
Jag Shur

The complex relationship between dry powder inhaler (DPI) devices and carrier based formulations determine pharmaceutical performance are critically important issues to consider when producing generic DPI systems. The presentation will explore both device and formulation attributes that may guide the development of in vitro comparability between test and reference product. Computational fluid dynamics (CFD) modelling and in vitro characterization by a multistage cascade impactor was utilized to provide engineering assistance in identifying and understanding the key performance attributes, which would influence the design and engineering in modifying a test DPI device. The material property attributes of micronised active pharmaceutical ingredients (APIs) and carrier lactose were also measured to design formulation that enabled in vitro equivalence of test and reference product across a range of different flow rates. The presentation will provide an insight into the importance of enhanced product understanding and the considerations required in the fabrication and refinement of a test DPI devices and carrier based DPI formulations that may provide a closer match to the aerosolization performance of the reference DPI device in achieving bioequivalence across all territories.

DOWNLOAD PRESENTATION

13CL1
Experience with registration of an imported inhalation drug product in China
Hong Yin

In China, drug registration includes Clinical Trial Application (CTA), performance of a local clinical trial, and finally submission of the New Drug Application (NDA). For new drug products (not generics), the full drug registration process, including performance of the clinical trial, can take 4-6 years. Pharmacokinetic (PK) and phase III studies in Chinese subjects are required for registration of the majority of imported drug products.

For inhalation products, the registration requirements (procedure, documents) and the timeline for CTA/NDA in China are similar to the registration requirements of other products. A submission document contains sections addressing CMC (Chemistry, Manufacturing and Controls), pre-clinical and clinical information. Drug testing for 3 batches of product will be needed in the Chinese Health Authority's laboratory during registration. Review and approval of the CTA and the NDA involves the State Food and Drug Administration (SFDA), the Center for Drug Evaluation (CDE) and, the National Institutes for Food and Drug Control (NIFDC). Our experience with registration in China of an imported inhalation product will be discussed. The drug is a once-daily, long-acting beta-2 agonist (LABA) inhalation powder hard capsule for COPD treatment.

This imported inhalation product contains the formulation and a separate inhalation device which are packaged together in one commercial pack. Both the drug and the device need to be registered in China. For the drug registration, a CTA was submitted in 2007 and was approved in 2008. China participated in a multinational clinical trial prior to global approval. The NDA was submitted in 2010 after the availability of the clinical trial study report and a reference country approval. The NDA was finally approved in 2012. For the device registration, we submitted an independent device registration to the Chinese Center for Device Evaluation in 2010, and obtained the approval after 7 months. During the drug labelling discussion during NDA review with the CDE, we combined device registration information with drug labelling to link the two registration paths. Details of the drug registration process will be presented including review of the CTA, which included a panel meeting with the CDE. This meeting occurred 6 months after the initial submission, and included review and discussion of the clinical trial protocol - a 26 week, multi-country, double-blind, placebo-controlled, parallel-group study, with a total of 563 randomized patients, with the majority being Chinese subjects. During the NDA evaluation, the CDE focused on study results from Chinese patients and reference countries' approval. A question list was issued around 1 year after NDA submission. There was no panel meeting with the CDE during the NDA review. Quality testing of the product was performed in a Health Authority laboratory and the report submitted to the NIFDC for review. During this process, the NIFDC requested new information including acceptance criteria for drug substance related impurities in drug product.

Learnings and mitigation strategies from the experience will be discussed, including those related to reaching agreement with the CDE on aspects of the clinical trial protocol; understanding the registration environment; and the requirements and expectations for specific types of testing and specifications.

DOWNLOAD PRESENTATION

13IL16
High dose drug only respiratory delivery - novel approaches to understand aerosolisation of powders
Peter J. Stewart

The aerosolisation of drug formulations without excipients can be problematic due to the interactive nature of the drugs particles in a size distribution suitable for respiratory delivery. Drugs in particle sizes less than about 5 μm are generally cohesive due to the dominance of the cohesive interactive forces over the gravitational detachment forces. De-agglomeration and thus aerosolisation of the powder has been shown to be related to tensile strength of the cohesive structure of the drug mass. Tensile strength is related to particle size of the drug, the packing fraction of the powder bed and work of cohesion. The estimation of the tensile strength distribution using distributions of particle size, packing fraction and work of cohesion has been found to provide explanations of the aerosolisation behaviour of some powders. The purpose of this presentation is to explore the use of the surface and bulk properties of cohesive powder beds to interpret aerosolisation behaviour and to use these parameters to develop better strategies to improve the efficiency and reproducibility of high dose drug only formulations.

Aerosolisation of powders was performed from a range of inhaler devices with differing resistance (Rotahaler, Monodose Inhaler and Handihaler). The extent of aerosolisation was determined using de-agglomeration versus flow rate profiles, where the percentage de-agglomerated was determined using particle sizing of the aerosol plume by laser diffraction. Work of cohesion distributions were calculated from surface energy distributions determined using a finite dilution experiment in an inverse gas chromatography. The tapped volume distributions for each powder in four replicates were determined over 1024 taps by an automatic tapper. The primary particle size distributions were determined by laser diffraction in liquid media.

The outcomes of this research demonstrated that the relative de-agglomeration - air flow rate profile provided a tool to characterise the aerosolisaion of the cohesive material. The differing behaviours of the model materials used (lactose, salbutamol sulphate) was explained by the tensile strength distributions estimated using a Monte Carlo simulation from the particle size distribution, work of cohesion distribution and the packing fraction distribution. The research allowed the dominant parameter in defining aerosolisation behaviour, in particular the work of cohesion and the packing fraction, to be identified and provided a rational approach to improving dispersion. For example, where the work of cohesion of a drug was high, dry coating using magnesium stearate reduced the work of cohesion and increased aerosolisation. In other cases, where the work of cohesion of materials was similar, the differing extents of aerosolisation were explained by differing packing fractions due to change in particle shape.

The approach to understand the fundamental drivers that influence aerosolisation of drugs is important as it allows rational strategies to develop efficient and reliable formulations of drug only formulations to be developed.

DOWNLOAD PRESENTATION

13IL15
Commercial scale particle engineering led approaches to cost effective generic and branded respiratory medicines for the global inhalation market of tomorrow - translating academic theory into industrial reality
David Hipkiss

The asthma and COPD market is large and growing. Industry estimates suggest it was worth $22.5Bn pa in 2011 and will grow to $44Bn by 2016 at CAGR of 14.3%. COPD is predicted to be the world's third largest cause of death by 2030. The respiratory space has been historically dominated by the major pharmaceutical players who have total control of API, device, and captive manufacture. Unit pricing of these necessarily complex products is high because of limited competition and market based pricing policies. Consequently and due to the chronic nature of the disease states, the area is highly attractive to the generics and/or speciality pharmaceutical industry.

However there are multiple barriers to classical generic entry via directly substitutable products i.e. those which can be dispensed against prescriptions at the Pharmacy level. Despite many of substance of matter patents having, or shortly to be, expired, there are significant manufacturing, regulatory and new device interchangeability challenges in demonstrating therapeutic and bioequivalence and/or non-inferiority particularly for combination products. This varies from product to product.
Hence the opportunities for classical generic approval via conventional means are very limited, and with pressures on global government budgets, rapidly evolving reimbursement policies related to value rather than market- based pricing, and a demand from emerging economies and regions for access to better healthcare, there is a clear and pressing long term need for cost effective, respiratory medicines for a growing populous.

The Prosonix particle engineering approach to respiratory development has now translated many years of academic collaboration on fundamental science and in-house core research and development into a new commercial scale reality. This new reality represents a potential ideal solution to emergent global need, combining the best of all worlds of hi-tech, low cost manufacturing of high added value, optimally performing, difficult-to-make combination products in simple off-the-shelf already approved delivery devices.

Prosonix's presentation will present a series of in-house case studies of how it has been possible to combine cutting edge science, technology, manufacturing with emerging regulatory guidance to deliver a suite of products to support the emerging healthcare needs of tomorrow.

DOWNLOAD PRESENTATION

13IL14
Investigating primary and secondary processing behaviour of orally inhaled active pharmaceutical ingredients
Robert Price

Conventional methods of producing API for DPI formulations begin with batch crystallisation processes, which routinely use an anti-solvent to precipitate or crystallise the drug. The use of an anti-solvent alongside mechanical agitation during crystallisation can lead to poor mixing and local levels of high supersaturation resulting in heterogeneous particle growth. This in turn can lead to variability in particle size and morphology of the crystalline material. The isolated crystals then undergo high-energy mechanical processing such as micronisation to reduce the overall API particle size. The vast mechanical stresses within the micronisation process, coupled with relative inefficiency of this unit operation highlight the importance of understanding the properties of the primary crystalline feed material, in order to produce materials for inclusion in the final drug product with defined specification and functionality. The elastic-plastic properties of the crystalline API to be micronised plays a fundamental role in determining the resistance to fragment upon milling, therefore, this property defines the degree of particle size reduction of the primary crystals.

The Young's modulus represents a material's resistance to elastic deformation and has been reported to have a strong influence on the micronisation behaviour of solids. The atomic force microscope (AFM) has been previously shown to be able to determine the Young's modulus of organic crystals and measurements of the Young's modulus of materials to understand their milling behaviour has been investigated. However, there remains a paucity of data relating the influence of crystallisation processes on the Young's modulus of the resultant crystals, their micronisation efficiency and performance in carrier based DPI formulations.

In this study, crystallisation of fluticasone propionate (FP) was conducted using three different solvent/anti-solvent combinations to investigate the influence of different end-solvents on the Young's modulus of the resultant crystals, their micronisation behaviour and in vitro performance in carrier based dry powder inhaler (DPI) formulations. The Young's modulus of FP crystals produced using different end-solvents varied significantly ranging from 0.6 - 12.4 GPa. FP crystals with the lowest Young's modulus required four micronisation passes to reduce the particle size of the primary crystals to less than 5 μm. In contrast, FP crystals with the highest Young's modulus required just one-pass through the microniser to achieve the desired particle size. Furthermore, the resultant micronised materials were determined to have different cohesive-adhesive balance values, which supported differences in their respective DPI formulation performance attributes. The study highlights how crystallisation conditions affect primary and secondary processing of active ingredients intended for delivery to the lung via a DPI and therefore, drug product performance.

DOWNLOAD PRESENTATION

13SA3/13PS49
The development of dimple shape dry powder carrier for ethambutol dihydrochloride
Md Iftekhar Ahmad

The objective of this study was to prepare dimple shape dry powder carrier of ethambutol dihydrochloride to administer by inhalation to the infected site with high concentration in lung while simultaneously minimizing both peak serum levels and exposure to other body tissues.

Ethambutol is primarily a bacteriostatic and anti-tuberculosis agent. The oral dose of ethambutol dihydrochloride is 20 mg/kg with MIC of 2 μg/ml. Due to this high dose; it causes visual impairment and lead to complete blindness. However, if it is administered in aerosol form as a dry powder inhaler (DPI), the dose of ethambutol dihydrochloride is expected to be reduced drastically. Chitosan is a de-N-acetylated form of chitin; consist mainly of β(1-4)-2 amino-2-deoxy-D-glucose units. It is a biodegradable, biocompatible, non-toxic and mucoadhesive in nature. Spray drying was carried out to prepare dimple shape micro-size (1.2 μm) carrier powder. Carrier particles with rough surface particles are likely to reduce Van der Waals force of attraction and increase aerosolization properties of powder. The dimple shapes have grooves all over its body surface which provides good space for drug to bind over its surface and its dispersion in an oral cavity. The ethambutol dihydrochloride solution (1% w/v) was nanosprayed by nano spray dryer B-90 at 110°C and 85% spray rate. The chitosan solution (1% w/v) was spray dried through a 1.5 mm nozzle using a mini-spray dryer B-290 under different inlet temperatures (80-150°C) with a feeding rate of 3 ml/min. Five carriers of different ratios were prepared by physical mixing. The physico-chemical properties of different formulations were analyzed by SEM, DSC, and FT-IR. The depositions of drug in different regions of lungs were determined by the Anderson Cascade Impactor (ACI). The separation of drug with the carrier inside the lung was determined by using ultracentrifugation method. The drug exhibited smooth, free flowing and spherical surface having size of 222 nm. The carrier showed the dimple surface when solution was sprayed at high inlet temperature (150°C) with low feed rate. The SEM image showed the adhesion of drug with the carrier on its groove as well as on its surface. The binding of drug with carrier depends on the amount of carrier available in the formulation. DSC thermograms. All formulations had shown amorphous halo because at high temperature carrier got melt and acted as a solvent for the drug to dissolve in it. FT-IR indicated the complex formation between drug and carrier. All the formulations showed content uniformity in acceptable range (99-107%). The emitted doses (ED) of different formulations were between 80-85% and have the mass median aerodynamic diameter of 1.9 μm. The separation of drug with carrier was depended on the drug: carrier ratios in formulation; formulation with low ratio of carrier got separated at low RCF while higher ratio separated at higher RCF.

DOWNLOAD PRESENTATION

13SA1/13PS47
Controlled antisolvent precipitation and characterization of itraconazole nanoparticles
Ka Yee Wan

Purpose: This study aimed to develop a consistent and stable nanoparticle formulation of itraconazole (ITZ), a triazole antifungal agent.

Methods: ITZ nanosuspensions were prepared using a four-stream multi-inlet vortex mixer (MIVM), inside which an organic solvent (dimethylformamide, DMF) stream containing ITZ and stabilizers/costabilizers was efficiently mixed with three other independent aqueous antisolvent streams (in a defined organic solvent to water ratio of 1:19 v/v) to create a supersaturation level high enough for triggering extremely rapid nanoprecipitation. Polyethylene glycol - polylactic acid (PEG-PLA) block copolymers and d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) were employed as primary stabilizers and cholesterol (CLT) as costabilizer. The resulting nanosuspensions were subjected to ultrafiltration to remove residual organic solvent, followed by addition of a protectant [sucrose, mannitol, lactose or hydroxypropyl-β-cyclodextrin (HP-β-CD)] prior to spray drying. Surface composition and morphology of the nanoparticles were analyzed by X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM), respectively. Particle size of the nanoparticles was determined by dynamic light scattering (DLS) technique before drying and after reconstitution of the dried powder with water.

Results: ITZ nanosuspensions with mean particle sizes less than 200 nm and polydispersity indices less than 0.3 were readily and reproducibly fabricated by the MIVM. TPGS and CLT in combination afforded the most stable ITZ nanosuspension with a mean particle size of ~90 nm, a drug loading of ~45% and an encapsulation efficiency >99%. XPS analysis revealed an increase in the ratio of hydrophilic to hydrophobic segments of the TPGS on the nanoparticle surface after two hours of storage, indicative of the molecular rearrangement of TPGS with their hydrophilic groups orientating towards the particle surface. AFM revealed that the ITZ nanoparticles were roughly spherical in shape and the observed particle size was consistent with the DLS data. Among all the protectants tested, only HP-β-CD was found to be effective for preserving the size (<50% increase) of the nanoparticles when subjected to spray drying. As shown by SEM, the spray-dried product appeared as micron-sized particles with smooth surfaces, reflecting a homogeneous dispersion of the nanoparticles within the HP-β-CD carrier matrix. A higher concentration of nanoparticles or HP-β−CD used in spray drying tended to afford better particle size preservability for the dried nanoparticles.

Conclusion: The present work clearly demonstrated that the MIVM is an effective tool for generating consistent ITZ nanoparticles with particle size below 200 nm, and judicious selection of stabilizers and protectants is critical to ensuring the stability of nanoparticles following precipitation from solutions and during the subsequent spray drying process.

DOWNLOAD PRESENTATION