Design and development of a novel dry powder inhalation (DPI) aerosol drug delivery device for the treatment of acute asthmatic episodes

Annemarie K. Alderson, Annie Saha, Stephanie T. Shaulis, Robert J. Toth

BioE 1160/1161: Senior Design, University of Pittsburgh, Department of Bioengineering

April 29, 2005

Abstract

Asthma is a chronic, constrictive disease of the intrapulmonary airways affecting a significant and increasing number of individuals. Pharmaceutical therapy of acute asthmatic episodes with drug delivery directly to the respiratory tract through oral inhalation has been successfully implemented in practically all asthma sufferers. The use of either metered-dose inhalers (MDIs) and/or dry powder inhalers (DPIs) is ubiquitous among the vast majority of individuals with the condition. However, current devices of these types fall short of desired patient preferences, particularly in mobility and robustness. Therefore, was the goal of this project to design and develop a dry-powder type, single-dose, disposable inhaler. The device is completely self contained, ruggedly constructed, lightweight, small, ergonomically designed, and actively mobile. The device is applicable to asthmatic individuals who desire a temporary alternative to traditional devices during physical activity and/or in extreme environmental settings (running, bicycling, swimming, skiing, various sports and outdoor activities, at the beach, etc.). The device was designed utilizing Solidworks solid modeling software, and computationally analyzed with the COSMOSFloWorks computational fluid dynamics (CFD) functionality within Solidworks. Prototyping of the device was performed through Quickparts.com – a custom rapid prototyped parts supplier. The functional prototype was developed within the time table of the project, and aerosol dispersion and flow testing was conducted in the Aerosol Drug Delivery and Pulmonary Biomechanics Laboratory under the direction of Timothy E. Corcoran, PhD at the University of Pittsburgh. The time table for detailed design, prototyping, and testing was four months (January – April, 2005).

Keywords: Asthma; Bronchodilator; Aerosol; Nebulizer; Metered-does inhaler (MDI); Dry powder inhaler (DPI); Product design specifications (PDS)

Contents

1. Introduction………………………………………………………………………………...... 02

2. Asthma……………………………………………………………………………………….. 03

2.1. Characterization of the disease…………………………………………………………. 03

2.2. Methods of treatment…………………………………………………………………… 04

2.3. Principles of drug delivery to the respiratory tract……………………………………... 06

3. Oral inhalation aerosol technology ………………………………………………………….. 07

3.1. Nebulizers………………………………………………………………………………. 08

3.2. Meter-dose inhalers (MDIs)…………………………………………………………….. 09

3.3. Dry powder inhalers (DPIs)…………………………………………………………….. 12

4. Design considerations………………………………………………………………………... 13

4.1. MDIs vs. DPIs…………………………………………………………………………... 13

4.2. Aerosol generation mechanism…………………………………………………………. 14

4.3. Product design specifications…………………………………………………………… 14

5. Design methods…………………………………….………………………………………… 17

5.1. Initial design decisions………..…………………………………………………………. 17

5.2. Solid model design methodology…………………………………………………….… 18

6. Design results…………………………………………………………………..…………….. 24

7. Design analyses, modification, and validation…….. ……………………………………….. 26

7.1. Model-8 analyses……………………………………………………………………….. 26

7.2. Prototype modifications………………………………………………………………… 29

7.3. Final analyses and validation…………………………………………………………… 32

8. Conclusions…………………………………………………………………………………… 34

9. Acknowledgements…………………………………………………………………………… 35

References……………………………………………………………………………………….. 35

1. Introduction

One of the most chronic conditions affecting individuals in the United States is asthma. Simply defined, asthma is an immuno-mediated condition characterized by increased resistance to airflow in intrapulmonary airways in response to various non-specific chemical and physical stimuli [1]. The condition manifests itself in common symptoms including breathlessness, chest tightness, nighttime and/or early morning coughing episodes, and episodes of “wheezing” – exaggerated and forced breathing [1,2]. Asthma is a rapidly escalating pulmonary disease.

The prevalence of asthma has been increasing since the early 1980s for all age, sex, and racial groups [3]. The overall age-adjusted prevalence of asthma rose from 30.7 per 1,000 population in 1980 to a 2-year average of 53.8 per 1,000 in 1993-94 [3]. This represents an increase of 75 percent [3]. The prevalence among children ages 5 to 14 increased 74 percent, from 42.8 per 1,000 in 1980 to an average of 74.4 per 1,000 in 1993-94 [3]. Among children up to four years of age, asthma prevalence increased 160 percent, from 22.2 per 1,000, the lowest prevalence among any age group, to a 2-year average of 57.8 per 1,000 in 1993-94, the second highest prevalence behind children 5 to 14 [3]. Thus, asthma is an obviously increasingly common condition.

As of 2001, 20.3 million Americans have reported suffering form asthma [4]. In terms of the effects of the condition on the healthcare industry, in 2000 alone there were 10.4 million asthma-related visits to outpatient hospital clinics and private physician offices, 1.8 million emergency room visits for asthma related problems, 465,000 inpatient hospitalizations, and 4,487 deaths attributable to asthma-related complications [4]. This translated to an estimated $14 billion in related healthcare costs that year [5].

As the above statistics indicate, the market for asthma-related medical devices is large and is increasing along with the increasing trends in the incidence of the disease. In addition, the current options in treatment technology do not completely satisfy the needs and preferences of individuals afflicted with the disease. This is especially true in the area of prescription drug delivery. In particular, while the pharmaceutical agents and the devices utilized to deliver those agents to the respiratory tract – the primary site of localized asthma treatment – have found widespread effectiveness in treating the condition through symptom mitigation; the delivery devices, inhalers especially, possess a number of significant limitations that oftentimes prove a hindrance to asthmatic individuals. These limitations include limited environmental exposure; reduced or precluded functionality under non-ideal operating conditions; fragile construction; delicate operating mechanisms; inconvenient and inefficient shape, size, and weight; and significant impairment to active portability. Therefore, it was the goal of this project to develop, design, prototype, and test a novel aerosol drug delivery device that addresses the limitation delineated above.

This document presents the preliminary research conducted in preparation for the design and development of the proposed device as well as the methods and results of the design work itself. This includes a brief review of asthma, characterization and treatment of the disease, a review of the current oral inhalation technology, the technical considerations implemented in the device design, a detailed project plan outlining the design methods, and the analyses and validation of the developed device.

2. Asthma

2.1. Characterization of the disease

A diagnosis of asthma is generally considered appropriate in patients in whom episodes of wheezy breathlessness, with intervals of relative or complete freedom from symptoms, can be shown to be associated with variations in resistance to flow in intrapulmonary airways [1]. In such patients, abnormal increases in expiratory airflow resistance can usually be demonstrated in response to various non-specific chemical and physical stimuli [1]. These stimuli have been shown to include triggers as varied as secondhand smoke, dust and dust mites, environmental air pollution, cockroach allergen, pet dander and fur, mold and mildew, high air humidity, freezing temperatures, thunderstorm-generated ozone, food and/or drug additives, emotional states, and strenuous physical activity [6]. Moreover, asthma may develop in individuals who suffer from other chronic bronchopulmonary diseases, such as bronchiectasis or emphysema, in which the specific pathology of the disease induces asthmatic symptoms in the diseased respiratory tract [1,2].

Antigen-antibody reactions of several types, due to inhaled triggering stimuli, have been shown to be concerned in the pathogenesis of asthma [1]. The most frequent and probably the best understood of these reactions is that observed in a group of patients who have an inherited genetic susceptibility to develop hypersensitivity to a range of potentially antigenic substances as a result of the minor exposures to the small amounts inevitability present from time to time in respired air [1]. The resulting immunologic reactions are IgE immunoglobin mediated [1,2]. Other types of antigen-antibody reaction have been shown to be involved in some cases of asthma. For instance, heavy exposure to inhalation of certain organic and inorganic compounds can cause sensitization, not dependent upon any genetic susceptibility in the person exposed, and accompanied by the development of precipitating antibody; and subsequent exposure may then give rise to the common asthma symptoms [1,6]. These symptoms usually include any number of the following; breathlessness, chest tightness, coughing episodes, and episodes of wheezy dyspnoea, otherwise known simply as “wheezing” [1]. All of the above symptoms are manifestations of the increased resistance to airflow due to constriction of the respiratory tract, particularly the bronchioles [1,6].

Upon IgE immunoglobin reaction in the respiratory tract, a number of inflammatory mediators play an interactive role in the constriction of the bronchioles [7]. Acute asthmatic episodes are now thought to be connected to IgE reaction through the actions of mast cells, which are pervasive in bronchial tissue [7]. Mast cells are known to possess an excess of 10,000 high affinity receptors for activated IgE [7]. Once mast cells bind with IgE, they have been shown to secrete a number of inflammatory chemicals including histamine, various leukotrienes, and various prostaglandins [7]. These substances have been linked to smooth muscle contraction in the bronchioles, thereby inducing bronchoconstriction and thus asthmatic episodes [7].

The other major triggering mechanism for asthma is exercise and hyperventilation inducement [8]. There are two major schools of thought on the mediation of exercise and hyperventilation induced asthma, both of which provide explanations for triggering mechanisms in addition to the possibility that the increased breathing rate associated with exercise and hyperventilation simply might bring in more external chemical stimuli [8,9]. It has been shown that changes in the physical environment inside the respiratory tract due to rapid breathing, particularly changes in air temperature and humidity, can incite bronchoconstriction through changed osmolarity within the bronchial tissue [8]. Changes in osmolarity have also been linked to mast cell recruitment and activation in the respiratory tract [8]. The second school of thought involves direct neurological mediation of bronchoconstriction [9]. The respiratory tract is innervated throughout its length, but especially the bronchial regions [9]. The nerves are part of the autonomic nervous system and retain partial control of bronchial tone through smooth muscle cell action [9]. In terms of sole nervous effects contributing to asthma, several types of autonomic defects have been proposed including enhanced cholinergic, a-adrenergic, and non-adrenergic non-cholinergic (NANC) excitatory mechanisms, or reduced b-adrenergic and NANC inhibitory mechanisms [9].

Despite the varied mechanisms implicated in the development and perpetuation of asthma, they have, for the most part, been reconciled into a contributory theory, where a number of different triggering stimuli coupled with immuno-inflammatory, neural, and physical processes all play a role in the condition [7,9]. The complex interplay of triggering stimuli and physiological response in asthma results in complicated treatment methods for the disease.

2.2. Methods of treatment

Despite the chronic nature of asthma, it is most commonly treated in an acute manner. This is primarily due to the lack of development of any successful disease mitigation therapies [10]. Therefore, all pharmacological treatments for asthma are disease or symptomatic control measures [10]. The lack of an effective treatment in eliminating the pathology does not preclude total recovery from or elimination of the disease in afflicted individuals. Complete recoveries with apparent elimination of all symptoms have been observed in some asthmatics – predominately in children [3]. However, this occurrence cannot be correlated to pharmacological therapy and is most likely a case of so-called “growing out of the disease” [3]. The control medication for asthma is often classified into four categories; immunotherapy or allergy desensitization shots, anti-IgE monoclonal antibody therapy, long-term control medications, and quick-relief medications [10-12].

The first two classifications involve mitigation of the immuno-inflammatory reactions implicated in asthma [12]. Immunotherapy involves a series of injections of asthma triggering allergens to induce desensitization [12]. Anti-IgE injections, such as omalizumab (Xolair), block the action of IgE immunoglobin and thereby eliminate the initiation of the inflammatory reactions implicated in asthma [12]. These therapies are less common in the treatment of asthma than are the aerosol-type medications.

Long-term control medications are typically taken on a daily or twice-daily basis to achieve and maintain control of persistent asthma [10]. They include corticosteroids, long-acting b2-agonists, leukotiene modifiers, sodium cromoglycate, and theophylline [10,13]. Table-1 below presents the most common drugs in each category.

Table-1: Common drug treatments for asthma [10-13].

Drug name / Brand name / Drug type
Long-term control medications
fluticasone / Flovent / inhaled corticosteroid
budesonide / Pulmicort / inhaled corticosteroid
triamicinolone / Azmacort / inhaled corticosteroid
flunisolide / Aerobid / inhaled corticosteroid
beclomethasone / Ovar / inhaled corticosteroid
salmeterol / Serevent / long-acting b2-agonists
formoterol / Foradil / long-acting b2-agonists
montelukast / Singulair / leukotiene modifier
zafirlukast / Accolate / leukotiene modifier
sodium cromoglycate / Intal / mechanism not known
nedocromil / Tilade / mechanism not known
theophylline / Uniphyl / mechanism not known
Quick-relief medications
albuterol / Proventil/Ventolin / short-acting b2-agonists
pirbuterol / Maxair / short-acting b2-agonists
ipratropium / Atrovent / anticholinergic

Corticosteroids act in an anti-inflammatory manner by inhibiting local recruitment of mast cells through suppression of the formation of cytokines – the chemical mediators responsible for the progression of the asthmatic reaction from IgE-antigen complex to smooth muscle contraction [10]. Long-acting b2-agonists induce bronchodilation by binding to b-adrenergic receptors in bronchial tissue and inducing smooth muscle cell relaxation [10]. Leukotriene modifiers function by blocking leukotriene production or interfering with receptors in the airways. Inhibited leukotriene action reduces inflammation of the airways and thereby lessens the symptoms of asthma [11]. Sodium cromoglycate, nedocromil, and theophylline are three drugs whose mechanisms of action are not well characterized but are known to effectively reduce asthma symptoms [11,13]. Sodium cromoglycate is especially effective. It is thought to prevent antigen-induced release of mediators from mast cells through an unknown mechanism, however, it has also been shown to possess bronchodilator properties through action on smooth muscles cells [13]. Effective control of asthma in 60-70% of patients is observed with sodium cromoglycate [13].

Quick-relief medications, otherwise termed rescue medications, rapidly stop the symptoms of an abrupt asthma attack [11]. A number of long-term medications also possess short-term effects, and thus, are utilized in a dual manner [11]. However, there are medications that act only in a short-term manner; the most common of these are listed in Table-1 [11]. These drugs act as bronchodilators that act rapidly to relax smooth muscle cells and dilate the airways [10,11].