Vanderbilt University
Department of
Biomedical Engineering
The Development of an Automatic Metered Dose Inhaler
Group 11:
Maria del Carmen Carrillo
Jennifer B. Struble
Loyrirk Temyiakarn
April 27, 2004
Abstract
Metered dose inhalers are used to deliver inhaled medication to patients both at home and in critical care settings. With increasing patient loads, it is often difficult for medical staff to keep up with the necessary dosages, especially for extremely sensitive patients who require frequent medication to maintain open airways during intubation. Presently, there are no automatic means of administering bronchodilator medication into the ventilation circuit of intubated patients. The goal of this project was to create such a device. In order to properly develop such a device, user specifications, hospital requirements, Food and Drug Administration regulations, and manufacturer guidelines must be considered and weighted. Homogenization of medication with the propellant was the first obstacle identified and most difficult to resolve. Through literature research and experimentation, it was determined that pneumatic cylinders were the optimal solution. Once the design was formulated, various measures were taken to ensure the model met safety regulations. The resultant design was constructed up to the prototype stage. The following step in the design would be to include a user interface for prescription entry and a number of monitoring mechanisms to ensure proper delivery.
Introduction
Bronchoconstriction, the tightening of the muscles around the airways, is a symptom of pulmonary-related diseases such as chronic obstructive pulmonary disease (COPD). However, the disease that is perhaps most widely associated with bronchoconstriction is asthma. Asthma ranks among the most common chronic conditions in the United States, affecting an estimated 14.9 million persons in 1995 and causing over 1.5 million emergency room visits, about 500,000 hospitalizations, and over 5,500 deaths. The estimated direct and indirect monetary costs for this disease totaled $11.3 billion in 19981.
Figure 1. Cross-sectional view of inhaler.
Also widely associated with bronchoconstriction is the drug generically known as albuterol. Albuterol is a bronchodilator used to treat bronchoconstriction and bronchospasm induced by reversible airway constrictive diseases such as asthma and COPD. Of the various forms in which albuterol is distributed, one of the most common is the metered dose inhaler.
Metered dose inhalers are used to deliver inhaled medication to patients both at home and in critical care settings. Prior to the delivery, the medication in the MDI canister must be well shaken. At home, patients may shake the canisters and self-administer inhaled medications through the use of a common plastic handheld actuator (Figure 1). In a hospital, it is often inappropriate or impossible for a patient to self-administer inhaler medication; the patient must depend on nurses or other qualified staff for administration medication. With increasing patient loads in hospital wards, it is often difficult for the staff to keep up with the necessary dosage intervals. This is especially true for extremely sensitive patients who require frequent medication to maintain open airways during intubation, such as asthmatic patients who must be sedated and mechanically ventilated. It is therefore desirable to have an electromechanical device that will ensure that medication in a MDI canister is homogenized with the propellant and can deliver the medication automatically as prescribed electronically.
Presently, there are no automatic means of administering bronchodilator medication into the ventilation circuit of intubated patients. A nurse or doctor must physically administer the dosage necessary for the patient each time it is needed. The medication comes in a canister containing a microcrystalline suspension of albuterol in propellants with oleic acid totaling 17 grams. Each actuation releases 100 micrograms (mcg) of albuterol, 90 mcg of which is estimated to reach the patient2. The canister must be shaken to homogenize the medication with the propellants prior to delivery; a device to administer this therapy must therefore accomplish this before actuation to ensure delivery. Such a new medical device is subject to the requirements outlined by the FDA for different classes of medical devices. In this case, the device falls under the Class II specification.
Methodology
The medical staff involved would like a device that not only homogenizes and actuates, but also verifies the delivery of the medication. A prescription entry interface is required to determine the amount and frequency of medication delivery. This interface should include some error checking software, which will help prevent improper dosage. Furthermore, the device should include a counter that keeps track of the number of actuations that have occurred since the canister was placed. This will advise the user as to when a new canister is needed. This feature reduces the possibility of false positives when determining if the medication was in fact delivered. A Quality Function Deployment (QFD) analysis was performed in order to verify that technical design requirements as well as consumer needs were addressed in the design (Appendix A).
Since it was known that some medication is lost in the delivery process and that there are homogenization issues, experiments were conducted in order to investigate them. The initial testing was done in order to determine how much shaking was required for homogenization. It was also investigated whether vigorous shakes would be more beneficial than soft shakes. It was determined that soft shakes were equally as effective as vigorous shakes for the purpose of homogenization. Soft shakes were done in a smooth motion that ranged within the maximum height limit of one inch. The vigorous shakes consisted of a brisk motion ranging about 5 to 6 inches. A clean piece of glass (4” x 6”) was positioned orthogonal to the table surface. The plastic handheld manual actuator was shaken in various methods in order to perform the tests. A resettling period of 2 minutes was observed thus isolating actuations as independent of each other.
Due to the nature of this experiment, quantitative results are difficult to assess. Qualitative analysis of spot density and diameter were therefore the best option for comparison. After careful observation, it was determined that vigorous shakes were no more effective than soft shakes. The average size spot was about the size of a quarter, or about 24 mm. A threshold was noticed in both forms of shaking. For vigorous shakes, additional shakes after the first three did not improve the resultant spot area or density significantly. Five shakes was the observed threshold for soft shakes.
Results
The design began with acquiring a general understanding of albuterol and how it is administered to sedated, ventilated patients in hospitals today. From a mechanical standpoint, the main obstacle was creating a method for homogenizing the drug with the propellant prior to actuating the canister. Various approaches investigated for a solution to the homogenization problem included the use of a vibration device, a pulse vortexer, or a spring-loaded agitator. The initial ideas were outlined using Innovation Workbench to identify any variables that may have not been considered (Appendix D). After these avenues were researched, other options arose that proved to be more efficient. Pneumatic cylinders were determined to be the most beneficial for homogenization. A Quality Function Deployment analysis was created in order to further investigate the final design (Appendix A).
The prototype that was built can be seen in Figure 3. This image was created using OmniGraffle diagramming software6. This diagram was created very explicitly to explain the entire design and how it fits in with currently used chambers in the ventilation circuit. The device uses two pneumatic cylinders to properly administer albuterol medication. One cylinder is the homogenizer, which shakes the canister to a total of five times in order to properly homogenize the medication with the propellants. The second cylinder serves to actuate the canister and induce delivery of medication into the ventilation circuit where it will be pushed by the ventilator through the tubing. A solenoid valve controls each cylinder. The valves control the flow of air in the pneumatic cylinder to determine whether the piston is extended or retracted. Utilizing the AeroChamber® MV, aerosol holding chamber7, our device docks above the actuation slot allowing for homogenization and proper docking to ensure actuation and medication delivery.
Marketability
The National Institutes of Health (NIH) estimated that 500,000 people were hospitalized that had asthma or COPD in 19951. A different study showed that of admitted patients 1 out of 25 was mechanically ventilated with a need of bronchodilation medication8. A combination of these numbers provides that in the US approximately 20,000 patients per year can benefit from our device. The prototype was built using Festo pneumatics and control valves, valued at about $150 for each set. The casing that was chosen was bought for $25. Adding in the incidentals like padding and the various circuit components the final prototype cost about $360. Estimating these costs over such a small number of patients per year leads to higher manufacturing costs. The projected cost for each device including some royalties for Vanderbilt is estimated to be $600 market value.
Safety Considerations
According to the FDA a medical device is: “an instrument, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part or accessory which is:
· Recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them.
· Intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals
· Intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of it’s primary intended purposes through chemical action within or on the body of a man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.”3
The device’s purpose is to administer albuterol automatically to mechanically ventilated and sedated patients. It fulfills the second criterion because it is intended for treatment of bronchoconstriction. It satisfies the last criterion because the administration of albuterol will affect the structure and function of the bronchi by causing them to dilate and therefore deliver more oxygen to the alveoli.
The FDA further divides the devices into three different classes, each with separate sets of regulations; of these, the device falls under Class II. The FDA defines Class II devices as not life sustaining; however, “general controls alone are insufficient to assure safety and effectiveness, and existing methods are available to provide such assurances. In addition to complying with general controls, Class II devices are also subject to special controls.”5
General controls include:
1. Establishment Registration (use FDA Form 2891) of companies, which are required to register under 21 CFR Part 807.20, such as manufacturers, distributors, repackages and relabelers. Foreign establishments, however, are not required to register their establishments with FDA.
2. Medical Device Listing (use FDA Form 2892) with FDA of devices to be marketed.
3. Manufacturing devices in accordance with Good Manufacturing Practices (GMP) in 21 CFR Part 820.
4. Labeling devices in accordance with labeling regulations in 21 CFR Part 801 or 809.
5. Submission of a premarket notification [510(k)] before marketing a device. 3
In order for the device to come to market, clinical testing must be done to verify that it will not harm any patients, but rather serve as an aid for nurses and medical personnel. In order to conduct a clinical trial, an institutional review board must monitor the study and verify that all parties involved sign an informed consent form5.
The following three guidelines were specifically denoted for metered dose inhalers by the FDA.4
1. The metered dose inhaler/actuator device must be directly compared to a predicate device. For example, particle size distribution data should be gathered for the predicate and new device so that a direct comparison utilizing the identical particle sizing method can be made. Particle size distributions should be collected at three different times during the life of the canister, i.e., when the drug canister is full, 1/2 full, and toward the end of the canister lifetime.
Since the device was designed as an actuator only to be used with a pre-approved canister already on the market, this research does not need to be repeated.
2. Spray pattern and plume geometry are used to characterize primarily the performance of the valve and actuator. Spray pattern and plume geometry must be collected for the MDI/actuator assembly. Spray pattern should be determined by impingement of the spray on a thin-layer chromatography (TLC) plate. Since the observed spray pattern may vary with the distance from the actuator orifice to the TLC plate, a spray pattern profile should be determined at a distance between 2.5 and 7.5 cm from the mouthpiece for the new device and a legally marketed predicate device. Dimensional analysis of the geometry of the plume and the distribution of particles in the plume may vary depending on the configuration of the device. Plume geometry (side view of the plume) data for the new product and the reference product are optional but highly encouraged for both products.
Preliminary tests have been conducted on the plume geometry for the standard handheld device on glass with marginal success. In order for this device to be approved, evidence from similar tests using the actuator and mouthpiece in place would have to be conducted. The difficulty however is the use of the spacer in the circuit. The purpose of the spacer is to hold the albuterol until the patient inhales. Without inhalation, the medication will remain in the tube and not form a plume pattern. Therefore, a method for inhalation with the chromatography plate in between the source of force and the spacer needs to be researched and developed.
3. The potency or the average amount of drug delivered per spray must be specified. Potency tests should be performed for each specific drug in the claims of intended use.
Literature shows that each spray from the canister delivers 90 mcg of albuterol. Standard dosage for ventilated patients is 5 actuations due to the potential loss in the tubing. Although there is no literature or data to confirm this practice, it is the rule of thumb that is exercised in hospitals. Utilizing this information, it was assumed that the device would deliver the same amount as the manual method since it will be located the same distance from the patient and be using the same spacer and sensor.