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1、Design and development of a novel dry powder inhalation(DPI) aerosol drug delivery device for the treatment ofacute asthmatic episodesAnnemarie K. Alderson, Annie Saha, Stephanie T. Shaulis, Robert J. TothBioE 1160/1161: Senior Design, Uni versify of Pittsburgh, De pa rtm en t of Bioen g i neeri ngA

2、prii29, 2005AbstractAsthma is a chronic, constrictive disease of the intrapuimonary 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 successfu

3、lly implemented in practically all asthma sufferers. The use of either melered-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, particular

4、ly 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

5、 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 (he beach, etc.). The device was designed utilizing Solidworks solid mod

6、eling software, and conipulaiionally analyzed with the COSMOSFloWorks computational fluid dynamics (CFD) functionality within Solidworks. Prototyping of the device was performed through Q - a custom rapid prototyped parts supplier. The functional prototype was developed within the time table of the

7、project, and aerosol dispersion and flow testing was conducted in (he Aerosol Drug Delivery and Pulmonary Biomechanics Laboratory under the direction of Timothy E. Corcoran, PhD at the University of Pittsburgh. The time table f)r detailed design, prototyping, and testing was four months (January - A

8、pril, 2005).Keywords: Asthma; Bronchodilator; Aerosol; Nebulizer; Metered-does inhaler (MDI); Dry powder inhaler (DPI); Product design specifications (PDS)Contents1. Introduction 02Asthma 031.1. Characterization of the disease 031.2. Methods of treatment 041.3. Principles of drug delivery to the res

9、piratory tract 06Oralinhalation aerosol technology 071.4. Nebulizers 081.5. Meter-dose inhalers (MDIs) 091.6. Dry powder inhalers (DPIs) 12Design considerations 131.7. MDIs vs. DPIs 131.8. Aerosol generation mechanism 141.9. Product design specifications 14Design methods 171.10. initial design decis

10、ions 17Figure-3: Basic components of an MDI system 20.Plastic MouthpieceFigure-4: Cutaway schematic of and MDI ()Current research and development on MDI systems primarily concerns the chemical propellants 20. Chlorofluorocarbons (CFCs) have been utilized as the chemical propellants in MDIs for almos

11、t 50 years 20. There are three different CFCs that have found applicability in MDIs: CFC-11, CFC-12, and CFC-114 20. However, due to concern over environmental effects of CFCs the FDA in conjunction with the EPA has set a series of standards governing the phase-out of CFC-MDIs |20. Specifically, onc

12、e two non-ozone-depleting propellants are marketed with identical or superior characteristics in MDIs, CFCs will be phased out of use in the devices 20. Two promising candidates receiving much attention are from the hydrofluorocarbon family: HFA 134a and HFA 227ea 20. These propellants along with th

13、e CFCs (Figure-5,Table-3) account for all chemical propellants encountered in all MDI applications (Table- 4).Figure-5: Chemical structures of CFC and HFA propellants 20.Table-3: Physicochemical properties of MDI propellants 20.PrcpertyCFC IICFC 12CFC 114UFA B4aIH-A 227eaIknbiv p?ini fC)24-304-26-16

14、jpur preMirc (klUiw566IS2572390Erthalpy vap. (kJ /nol)25 117 222 A1X6196PoAartfvIXclectfic23212.29.541Dipole RKCTKflt045Q5IQ5S2.112Induced pdmzilicn (tn1 twr,XlH,)282J326 1&Suluhhn |xinmetcf1 IlikUbcaxI uiiKi756d66qKauri Bui;函 1 vali?601812913IxigP (act n ；iicr 12 JO2218M2.1Water ilubilih* ippim1301

15、30HO2200610LlijMi pkur14911471231 42isaWmPeiT)045Q30QWH2IQ27Surfxe leiiMiti imN m)IK9IIX7Table-4: Common marketed MDIs and their chemical composition 20.llKr.ip?ulicIXiipSurftnK exapi citsPhp?ll;inlPmul.iticn01*Rrtmdwddaior%MaxiiirPitbuiefolSuibiiH 1 IfMlcateCFC II. CFT 12Max;uf AUululccPitbulefol 4

16、c?l.CFC 11. CFC 12Soil lollenldnAlhukfol AiltilcOleic MidCFC II. CFC 12Sufnucnnr/.Mhukfol AilLtfcNracUFACortfc0swr(ahAer-bdHuniAhdeSoibilm itmIcmIc. avnlhdCFCI 1.(1( IZ CFC 114SupjiwcnArmx1rnamcmolrue acetonideCFC IZ! w/u ethanolSiifVIlMCtlBctlmrnlRevlKiKlIunoiic 上p7tuieOleic 4ciilCFC II. CFC 12Bcvu

17、lick UN)Bcl ciKlLnuiic kituteOleic 4viiCFC II. CFC 12SUVIIMCIIncnvfil 44. IIH. 2201 lutKotoiie |*tipcuieCFC II. CFC 12QY1R 50. IbOBcvljl!i；nonc AphputuiiUFA IMx cdi4KlSokluuiQYKR /uiolMkf 5a ICODkjllutunc K.hprcpkituieIII A IMx eliaalSoklioiijiicefilBcvlcciuiliiiiiiiic hprcpkiiuie cLuliraieCFC II. C

18、FC 12mW；lnt.il(ronuhn M-diimCFC 11. CFC 12SiifvnMcciIliad?Xla*aul sodiumSiibrtMi imlraleCFC II. CK 12StifvnMcnThe design and development of MDI systems is complicated by the necessary integration of numerous principles within one device 21. An effective MDI must integrate a pressure vessel, nozzle,

19、valve assembly into one device that is intuitive to operate and which provides a conformable interface with the mouth of a user. Furthermore, the chemical principles governing the drug/excipient/propellant mixture and the fluid mechanical principles governing the fluidization of the aerosol must be

20、accounted for. Consequently, it is understandable why a successful design has been fundamentally unchanged for over 50 years.3.3. Dry powder inhalers (DPIs)A dry powder inhaler (DPI), like a metered dose inhaler, is a handheld device that delivers a precisely measured dose of asthma medicine into th

21、e lungs. Both quick relief medicine (inhaled bronchodilators) and long-term control medicine (inhaled corticosteroids) can be delivered to the airways using a DPI 22. Unlike metered dose inhalers, where slow inhalation is needed to acquire the full benefit of the medication, DPIs require the user to

22、 breathe in quickly and forcefully to automatically activate the proper flow of medication 22,23. Since there are no propellants used in DPIs, the user must inhale with more force than when using a metered dose inhaler 23. It is usually recommended that to receive full benefit from a DPI, the user s

23、hould hold his or her breath for approximately ten seconds (or longer, if possible) after inhaling 23. It is important that the user does not breathe out through a DPI, because the moisture in the breath can cause powder agglomeration thereby clogging the mechanism, making it less efficient for, or

24、precluding, future uses 22,23.In a DPI, the asthma medication comes in a dry powder form 22,24, A small capsule, disk, or compartment inside the inhaler device is used to hold the medication 122,241. Manufacturing of DPIs for drug administration requires powders with desirable characteristics |22. S

25、pecifically, as noted above, upon aerosolization, the powder particles must be within the 0.6-5 pin range 22. In order to ensure compliance with this requirement, a number of processing methods are utilized to generate powders of proper properties 22. These methods include spray drying, spray freeze

26、 drying, controlled evaporation of droplets, solvent precipitation, recrystallization, fluid energy milling, and nano-milling 22. In addition to the drug powder, DPI formulations often include a number of additional additives - termed excipients as in MDI technology 22. These substances include lubr

27、icants or anti-adherents which minimize agglomeration upon aerosolization, desiccants, and for some drugs carrier particles 22. The most common dry powder excipient is lactose 22. Fine lactose (-5 pm) can function as a lubricant and as a carrier particle depending upon the specific formulation 22. A

28、s a lubricant, lactose functions to ensure particle dispersion upon inhalation by interfering with drug particledrug particle interactions 22. As a carrier, it functions as a substrate to which the drug compound is immobilized 22. The lactose-drug complex is then inhaled and deposits in the respirat

29、ory tract 22. Because DPIs utilize powdered medications, the need to keep them dry is crucial. As such, DPIs should not be stored in damp environments. Moreover, one of the major drawbacks to DPIs is their incompatibility with humid environments.Many types of DPIs are currently available and each ha

30、s a different operating mechanism. Consequently, there is no one general mechanism that could be described as was the case with MDIs. Furthermore, a description of each mechanism of even the most common DPIs is beyond the scope of this report. However, the major types bear mentioning. Some DPIs, inc

31、luding Inhalator, Spinhaler, and Rotahaler, must have the medication loaded each time they are used |22|. Others, such as Diskhaler, have pre loaded disks with a certain number of doses |22. Turbuhaler and Accuhaler are two DPIs that have as many as 200 doses stored in the device 22. Since all DPIs

32、rely on the force of the users inhalation in order to properly deliver the medication into the lungs, DPIs are not recommended for children under the age of five, people with severe asthma or those suffering a severe attack 22.The primary advantage of using a dry powder inhaler is that it is breath-

33、activated, so that the user does not need to coordinate activating the inhaler (dispensing the medication) with inhaling the medication 23. Instead, the flow of medication is activated by simply breathing in. Additionally, DPIs do not require propellants so they are more environmentally-friendly tha

34、n metered dose inhalers 22. Several disadvantages of DPIs are that they are often more expensive than the equivalent metered dose inhaler and they may be difficult and cumbersome to load 23. For example, the RotahaleiXs) requires the user to carry a supply of medication capsules with them because it

35、 can only hold one capsule at a time 22. If a single capsule is not sufficient to stop the asthma attack, the user must load another capsule in order to receive additional medication.The design and development of DPI systems is very flexible due to the fact that there arc countless mechanisms whereb

36、y dry powder capsules can be aerosolized and inhaled. A design is only limited by the constraints of the particular specifications for a device. Accordingly, it is understandable that there are numerous different DPI designs each with their own unique characteristics.4. Design considerationsAs the a

37、bove discussions indicate, there are numerous factors that must be considered when designing an inhalation drug delivery device based on aerosolization. However, the most pertinent consideration is by far the mechanism that will be utilized to generate the drug aerosol. Since the proposed drug deliv

38、ery device is to be by design mobile and for use in an acute, quick-relief manner, the choice of aerosolization mechanism is between that of an MDI or a DPI. Accordingly, what follows is a discussion of the benefits and detriments of the respective technologies and the logic and motivation behind th

39、e ultimate mechanism choice for the proposed device design.4.1. MDIs V5. DPIsIn terms of effectiveness in the delivery of asthma treatment medications, numerous clinical studies have reported the therapeutic equivalence of MDIs and DPIs 14. While differences in the deposition characteristics under c

40、ontrolled conditions have been demonstrated, the effective dose delivery is analogous between the two device types with established powder production and processing procedures for DPIs 25. Moreover, the goals of this project were not pharmaceutically related, but rather were simply to develop a devi

41、ce that met the deficiencies of current devices in terms of ruggedness, mobility, and versatility. Therefore, it was practical and logistic factors that weighed most heavily on the choice of aerosol generation mechanism.Ideally, it would have been prudent to design two devices, one MDI-based and the

42、 other DPI-based, each with analogous product specifications so that consumers would have the choice of which aerosol generation mechanism they prefer. However, given the scope and resources allocated for this project, such an undertaking was not accomplishable. Given the limited time frame, monetar

43、y resources, personnel, and production equipment for detailed design, prototyping, and testing; the project had to be especially limited in scope and of relatively simple execution. In order the meet these requirements, the overall device design was as simplified as possible. Considering the princip

44、les involved in the operation of MDIs versus DPIs; DPIs were clearly the less- complex, more straightforward to execute technology.A DPl-type novel device would be more rapidly designed, prototyped, and tested than an MDI-based design. An MDI design would require work with chemical propellants, mete

45、ring valves, pressure vessels, filling equipment, and a vast number of additional considerations that the DPI design would preclude. The design, prototyping, and testing of a relatively simple mechanical mechanism to activate a dry powder fitted within a casing that meets the design specifications i

46、s well within the constraints of the project. Therefore, a DPI-type device was chosen to be designed and developed consistent with the design specifications.4.2. Aerosol generation mechanismThe aerosol generation mechanisms in current DPIs are as varied as the number of different devices on the mark

47、et. Each device generates the aerosol based upon the functionality of the device, i.e. pre-loaded multi-dose disks, re-loadable devices - both multi-dose and single-dose, pre-loaded single-dose devices, etc. It was of crucial importance that the specific mechanism be consistent with the intended spe

48、cifications and operation of the device. Accordingly, the utilized mechanism was consistent with rugged, impact-resistant, and reliable operation. The general principles of the aerosol generation mechanism were similar to that of current technology, bul di fl erent enough to preclude patent infringe

49、ment.4.3. Product design specificationsAny respiratory drug delivery device must possess certain general characteristics and features to be a successful design. These characteristics and features are summarized in Tables-5 and 6 respectively 19. These characteristics and features are important to an

50、 effective design regardless of the specific type of mechanism utilized and the unique features of any one device. However, it is the mechanism itself and the unique features of a design that provide a market for the device. Therefore, it is important to design an aerosol drug delivery device with d

51、istinctive characteristics that improve upon existing devices or are novel.Table-5: Desirable characteristics of respiratory drug delivery devices of major interest 191.Stake holderMost desirable device characteristicsDrug patenteeProven deliver), platform lor simihr APIsAlready in production, but r

52、oom for patentable improvcnienh UsaNc by multiple patient populationsChildren, adults and elderlyDevice patenteeAccepts wide v；uicty of formulations without miyor reengineering Performance is insentive Io:DosePhysical and chemical properties of the API or carrierPatient behavior and breathing patter

53、nCan be customized aid brandedRculatinv agencyDevice wifrtyMinimal potential for abuse Prcdictable performancePayerCompetitive priciag with MDI for generic products Competitive prkig with cIoma! non-inhalcd therapyPhysician. pkaimacist orSimilar openition to existing device they ire familiar withoth

54、er healthMinimal training of pcxn idcr or paticnl requiredprofit ionalIntuitive to use in absence of tniining Good patient ACcq)tnBccPatientIntut ivr to use correct ly Convenient to cany and use Discrete and socially acceptableTable-6: Features of an ideal respiratory delivery device 19.DriverFeatur

55、ePatientRequired no connection to an external power sourceConvrnicnl and unohtmsivc to cairyQuiet and unobtrnsivc to use in publicRobust enough to survive routine transport, use and cleaning Does not require extra-ordinary inhalation maneuvers to use coirectlj-Has a dose counterHealth care providerI

56、ntuitive and apparvntly easy to useAppropriate technique can be taught easily, and mastcry of the technique can be visually confirmedFamiliar instructions for useRegulator)- agency andor devioe manufacturerAerosol generation technology docs not require use of excipients with no history of pulmonary,

57、 administrationBreath actuatedEmitted dose and aerosol size indqxrndcnt of inspiratory flow-rate Not detrimentally inflaenced by accidental exhalation through devioeDelivers a range of doses or drugs without major reengineering Provides a high level of dnig protection from water, oxygen and lightMul

58、tidoscReservoir, 1 months supplyUnit dose, at least 1 days supplyAencwol quality measuresReproducible emitted doseMinimum dnig retention in deviceRepnxiucible small particle sizeMinimal opportunity of accidental doable dosingAerosol exit propertiesLow oropharyngeal depositionLow exit velocity-Assure

59、d through-life performanceNo priming requirementRapid tail-ofT or lock oatMinimal number of small or precision partsNo detachable or accidentally inlialablc partsPatient selectable doseMinimum abuse potentialDi布cult to remove or replace intended drugOnly usable by intended ientTimed lock-out feature

60、sPayerCompetitive pricing (to existing therapy) Disposable unit (preferred in US) Refillable durable unit (less desirable)It is the improvements and novelty of a design that arc the important aspects of the product design specifications (PDS) for the purposes of detailed design work. While a complet

61、e discussion of the product design specifications for the proposed device is beyond the scope of this report, it is important to note those specifications that significantly impact the detailed design of the device.As previously noted, the device was of the DPI-type. Thus, the aerosolization mechani

62、sm was consistent with this specification. Moreover, the device was to be lightweight, single-use-only, disposable, and extremely rugged. These specifications had a profound effect upon the choice of materials of which the device will be constructed. In addition, the ergonomic and size properties sp

63、ecified for the device affect the external shape, which had implications for the internal mechanism. Thus, it was important to take time to work out the design details before subsequent prototyping and testing in order to eliminate any waste of the limited time or material/monetary resources.5. Design methods5./. Initial design decisionsThe actual development of any computational or physical prototype of the device was i