CA2126331C - Intelligent inhaler providing feedback to both patient and medical professional - Google Patents

Abstract

An inhaler device ( 100) for aerosol delivery of medication employs a microprocessor (220) and electronic sensors (230) for measuring parameters indicative of a patient's inhalation of airborne medication. The sensors produce output signals representative of parameters which determine the proper delivery of medication to receptor sites in the patient's lungs, such as, the rate of flow of air through the inhaler device to the patient's lungs, the duration of inspiration of the medication, and the volume of medication inhaled. The microprocessor is responsive to the output signals of the sensors and stores a record of inhalation events which can be retrieved remotely or by connecting the microprocessor to a display terminal (108). The microprocessor makes possible a display of data indicative of the delivery of medication for each inhalation event over a course of treatment, thus providing compliance feedback to both the patient and the medical professional.

Description

WO 93/128~3 PC~r/US92/10804 ' .~-,, 2126331 .

I~TEI.I,I~;E~T TN~ r~C~ tNG ~ nRa~:R TO BOT~I
PAT:~:BNT A~ DICAI, P~OF~8~3IO~

R~ JND OF ~ l~-V151~
Field of Invention The ~ield of the pres~nt in~ention relates generally to an inhaler device for aerosol delivery of medicine. ~ore particularly, the present inven-tion is directed to a de~ice for improving medica-tion compliance by providing feedback regardin~
correct and consistent usage of ~dicine inhalers tv a patient and/or professional such as a physician~ :
pharmacist, or therapist. The present invention is fur~her directed to a ~ethod by which such professional~ can track the usage of medicine inhalers between ~isits, and modify medicinal therapy bA~~~ on downlo~ of this information to - a clinical workstation allowing display and analysis.

The Prior Ar~
Getting patients to correctly use medicine inhalers is a major problem. Estimates indicate as few as one quarter of patients using inhalers do so correctly ~Orehek, J., "Patient Error in Use of Bronchodilator Metered Aerosols," Br~t~sh MQ~;Ca1 Journal, 1:76 (1976); Paterson, I.C. and G.K. Crompton, "Use of Pressurized Aerosols by Asthmatic Patients," British Medical Journal, 1:7677 (1976); Saunders, K.B., "Misuse of Inhaled Broncho-dilator Agents," British Medical Jou~nal, WO93~12~23 P~T/US9~/10804 t~

2 ~2 633 ~ - 2 -1:1037-1038 (196S); Shim, C., and ~.H. Williams, "The Adequacy of Inhalation of Aerosol from Canister Nebulizers;" ~he ~merican Jourr~l of MPAic~ne, 69:~91-894 (1980)]. In addition to ~ çce~e~ry patient morbidity and mortality, an unfortunate consequence is that patients may stop taking their ~edications because they are not ~e~ins any or enough bene~it. Conversely, having ~ailed to obtain expected benefits through prescribed usage, 80~e patients will overuse medications and thereby increa~e the risk of side sffects cau~ed by higher than nor~al do~ag~ (ç~g~, fungal inf~ction~ in the mouth and throat or nervou~ ~y~tem ~f~ct~ cAltge~ by medication absor~ed in the ga3trointestinal tract).
These problems are e~p*ci~ly ~vident in the case of aerosol phar~aceutical~ delivered by hand-held inhaler~. Hand-held metered dose inhalQr~
(~DI~) are a preferrad method of tr~atment for common respiratory ail~ents, ~incR the deliv~ry of ~edic~tion diractly to i~ int~nA~ ~ite of Act~on in the lung~ allows a reduction in dosage by an order of magnitude or gr~atar. However, certain of these com~o~ , such ~8 anti-inflammatory cortico-steroid~, may take many weeks of admini~tration before having a signific~nt effect. Moreover, the inhalation and breath-holding ~aneuver requirRd for ~ cçq-~ful deliv~ry of aero~ol to the lowar airway~
is counterintuitive and poorly under~tood by mo6t patients. Thus, a patient may be compliant in u~ing tha madication when pr~scribed, ~ut un~cc~ful in using it in the corract ~anner.
When therapeutic results are not ob~Aine~, it may not be evident to the phy~ician which step~) in W093/12823 PCT/US92/1~
f 2126~3~ :

the proce~ are the problem. Relevant que~tions, for example, are Nwas the medication not taken at all?", "was it taken at the corr~ct interYal~ and in ~LO~eX relationRhip to expo~ure to ~llergens or other irritants?", and "was the inh~lation perfor~ed correctly?".
Another problem the physician faces i~ how to interpret variability in therape~tic respon~e. I~
the v~riability due to ~o~e fundamental ~nqe in the pati~nt'~ condition (e~, the pati~nt now ha~ a~
lou ~Lade upper re~piratory infection) or is it cau~ed by difference~ in deliverQd medicat~on dosage?
~epo~ition of aerosol ~edication ~n the human lung i5 primarily deter~ined by ~wo pL~_Eere~, inertial impaction and gra~itational ~edimentat~on~
Impaction of aero~ol~ in the lung~ occurs pri~arily at airway bifurcations, and has been ~hown in scintigraphic studiQs to incre~ a~ ~ function of flow rate. Sedi~entation in~olve~ gravitational settling of a~roaol particl~s on the ~irways and al~eoli. 11~ , S.P., PaYi~, D., Garland, N. and S.W. Clarke, "Effect~ of Various ~h~lation Mo~c on the D~po~ition of Radioactive Pres~urized Aerosols,"
EU~ r J. Re8D;rAtOnr D~S. . S~D1e~ 119, 63: 57-65, ( 1982 ) demonstrated that the percentage of aero~ol depo~ited in the lungs of patients wa6 signifi~antly greater when the pat~ ents held their breath for ten E~onAC than when br~ath holding was only four -ecQnA~.
Thus, for aerosol to be ~o~o~ted in the lower airway~, the primary site of action for common medi-cations such as corticosteroids and bronch~ ators, PCT/~S92/10804 21263~

the patient must coordinate the relea~e of medica- ~
tion, inhale slowly enough to minimize 106s of ~edi-cine through impaction in the throat and upper air-ways, and br~ath hold long ~no~l~h to allow time for small particle~ to settle. In practice, this mean~
an inhalation rate below one liter per ~econd, and a breath hold for up to ten seconds.
A hand-held (e.a., metered or unit-do~e~
inhaler currently is a pa~sive device that provides n no information regarding the medication actually delivered. Orehek et ~ ound that only five of twenty a~thmatic patients correctly i~halQd. "The other 15 patients fail~d either to in~pire deeply or hold their breath a~terwards, or both, or poorly coordinated the puff and the in~piration.U Orehek et al., "Patient ~l~G~ in Usa of Br~nchs~ilator Metered Aero~ol~,~ Rr~t~h ~ l Journ~ 76, (1976).
For example, it has ~en found that in a group of 30 acute a~th~atic patient~ direc~ly ob~arv~d in a clinical setting, 47% (14 patients) used incorrect ique. Tha fourt~en pati~nts wi~h in~equate t~hniqus were then trained. Ten of them were ret~ted after an interval of one day to one month.
Five of the patient~ ~re ~till u~ing th~ir inhalers eo~.eetly; the other five had revQrted to their original ineorreet tee~iques. Shim, C., and M.H. Williams, "The Adequacy of Tnh~ lation of Aelo~ol from Canister Nebulizers,~ The Ameri~
Journal of ~edicine. 69:891-894 (1980).
The device and appro~eh deser~ed her~in would hav~ proYided im~ediate feedback to the patients that they had reYerted to incorrect uae o~ their W~3/12823 PCT~US92/10804 inhalers, and provided them with pecific ~~ nc~
as to what corrective action was requir~d. Thus, retraining would not have had to wait until their next ~isit to the clinic.
The present approach al~o fo ters the d~livery of a uniform do~e to the target ~ite3 of th~
patient'~ lungs upon each inhaler usage with the expectation of consi~tent therapeutic re~ponse.
Thu~, if the patient's ~ympto~s or condition changes, the physici~n can evaluate the change with r~ n~hle ~surance ~hat the difference i5 not simply due to a variation in ~edication do ~ge. By ~ak~ng data regardinq the patient's inhal~r use during the entire period betw~en clinic Vi8it8 available to the physician, therapy can be ~anaged on a more informed basis.
It ha~ been observed that, ~The lung pre~ents a significant barr~er to the ponetr~tion of drug particl~s of a size s~all ~ h to ~aximize thera-peutic efficacy." Padfield, J.~ Principl~ ofDrug Delivery to the Respiratory Tr~ctH, ~g D~livery to the Resu~r~tory Tr~Ct~ ~n~ton, D., and Jones, T., Qd., Horwood, Lundon (1987).
Padfield conclud~ "The design of delivery ~y~tem for admini~ter~ng drug~ to the lung can ha~e as much, or more, impact as the choice of drug." (i~-) Previous attempts to improve the ef~ectiven~ss of aero~ol medicine inhalers include a number of - device~ including ~ra~rs, aerosol holding chambQrs, flow-activated triggering me~h~n;cms, and dry powder generators.
The problem of medicine ~Ppocition in the mouth and throat can be alleviated in ~ome caaes by the W093/12823 PCr/US92/108~
2~26331 t~

use of a tube spacer, an extension tube inserted between the metered unit-do~e inhaler and he patient'~ ~outh. This pro~-e~ re ~till require~
coordinated patient action and in itself provides no f~e~h~k to the patient as to the Sl1rCePF or f~ilure o~ the overall sffort.
Another approach to improving NDI u~age i5 the use of chambers or reservoirs into whieh the aerosol ~ eh~rged prior to inhalation. Such device~
reduee the need for coordination of actuation and start of inhalation. A widely used device i~
described in Sackner, et. al., U.S. Patent No.
4,484,577, 1984. Thi~ device al~o provides an audible whi~tl~ when the in~piration rate i~ abov~ a fixed level. Th~ dev~ee f~ils to addrQss inter-patient variations in correct inhalation patterns, a~ well as the br~th-holding ~taqe. A co~mon draw-baek of all ehamber deviees i8 their bulk. Such deviees may not fit eonveniently in a pocket or pur~e, and many patiQnt~ are unwilling to u~e ~uch large devices due to ~elf c- ~~io~r ~ r~ . The proce~ in accorA~nee with the pre~ent invention ean be u~ed irre~peetive of whether a tube spaeer or a reservoir is u~ed.
Conventional ~y~tems al80 include ~everal inhaler deviees wh~ch a~dL~-- the eoordinati~n problem by incorporating a ~ean~ of trigger~ng the medication relea~e by the start of inhalation. Such devices have bean described by Wass, U.S. Patent No. D
4,664,107 1987, ~nd Johnson et. ~1., U.S. P~tent 4,803,978 1989. ~har.r, U.S. Patent 4,739,754, 1988 de~cribes a ~Suction Resistant Inhaler" whose design fosters a deep inhalation by the patient.

WO93~12823 Other conventional devices have incorporated electroomech~nical components in order to record the timing and date of usage for revi~w by a healthcare professional. Spector, et. al., "Compliance of Patients with Asthma with ~n Experimental AerQsoll2ed Medicatlon: Implications for Controlled Clinical Trials, n Jou~nal of Aller~y & Clini~
T~mlln~logy~ 77:6~-70 (1986) discloses the u~e of a nebulizer chronolog to I L 'OL~ the patient~ u~age of MDIs between clinic visits. Thi~ incorporate~
device for r~cording the time and datQ of each canister actuation for later review by physicians conducting r~-r-~ch on pattern~ of patient compliance. Thi deYice lacks the ~p~hility for lS ob~Ai~ any information regarding the inspiratory maneuver itself. Furthermore, since the intention of the ~tudy wa~ to record patient~' MDI usage patterns w~thout their knowl~dge, the device not provide any fe~Ah~k to the patl~nt~ regarding proper inhalation ~e~hnique.
S ~ilar de~ice~ are de w ribed by ~and et. ~1., - U.5. Patent 4,817,822, 1989, and ~çr~ertine, U.S.
Patent 5,020,527, 1991. The Rand device incorpo-rates a mechAn;cal rachet wheel and driving member 25 to drive an indicator of the number of actuations of an aero~ol cani~ter. The~ r~rtine device provides a timer and a counter for tr~ckin~ the number of and time between actuations.
In tha aforem~ntioned d~vice~ thQ time cour~e of air flow is not measured, nor is it comparad to the desired pattern for the ~pQC~fiC patiQnt a8 may be d~termined by a healthcare profe~sional. Thus, the~e devices addre6s only the a~pect of compliance WO~3~12823 PCT/US92~1~8~

- 8 - ;

relating to if and when the medicine was used. In order to A~.F~ whether an aerosol medication has been used effectively, it i8 n~cecr~ry to further deter~ine infor~ation regarding ~he pat~ent's coordination of actuation and inspiration, Yolu~e and flow rate of inspiration, and post-inspiratory breath holding.
In ~ummary, con~entional devices fail to adequately addrec~ ~he need for immediate patisnt feedback regarding multiple ~teps in the corr~ct u~e of inhaler~. The~e devices are al~o ~nAAequate in providing infor~ation to both patient and healthoare professional reqarding the critical factor~ which determine the sllcce~n of m~dicine delivery, including coordination of inhalation w~th actuation, inhalation flow r~te and duration of br~ath holding.
What i8 neeAe~ i8 a hand-held inhaler devlce which can monitor the complete time coursQ of airflow during ~n inhalation, and ~h~ pO~CB~a8 the r~r~hility to guide the pati~nt in it~ correct us~ge before, during, and after u~e~ What is al~o n~e~e~ i8 ~u~h an inhaler whose functions include the capacity to ~eCULd relevant information about the timing and nature of itR use for ~ubs~qu~nt review by a healthcare professional.

SUM~Y OF ~ V ~ ON
The pre~ent device detects how much air i8 inhaled through the inhaler with what time course (including such derived measurements as how much volume is inspired within the bounds of a gi~en flow range) as well as certain event such as the triggering of the release of aerosol. The system WO93~12823 PCT/US~2/10804 2126~

can be set up to co~pare the re~ultant time course to either (a) a st~nd~rd target envelope (e.q., one or more of flow, volu~e, and time) for that ~edica-tion or (b) a specific target ~nvelope for that particular patient programmed into the intelligent inhal~tion device by a healthc~re professional.
RAre~ on ~he ~p~ri~on, the ~uccess or failure o~
effectiYe inhaler actuation and aerosol inspiration can be signaled to the patient (e.a., vi ually or through sound) and may be ~e_o~ed with a t~me and date stamp for later ~co~ n~ and evaluation by a suitable healthcar~-profe~sional. ~n a preferred emb~di~ent of the i~vention, the device would al~o the ability to signal ~he patisnt to continue post-in6piratory ~reath-holdin~, and record the end o~ br~ath holding ~or U8e ~n interpret~ng the ~ ce~ of medication delivery.
In addition, immediate feedback can be ~upplied to the patient as to the specifie nature of any mistake~ made. For example, a ~ ge miqht bs given that the patient's ~h~lAtion was too rapid.
In a preferred embodiment of the invention suf f icient memory is provided to ~tore data from a large number of inhalation6. Thi8 aUtomatQd ~eCG~d may be u~ed in conjunction with a manual log kept by the patient (e.a., what,e~ent, such as eYro~re to an allergen, cau~ed the need to administer the medi-cation) or in a ~emi-automated fashion by h~ving the - patient or att~n~ant e~C9~9 event-related infor-mation into thQ ~nhaler device memory. An example of the latter would be the pr~ssing o~ a button in a certain pattern that would be ~-oc;ated w~th a ,. . : .

PCr~US92/10804 2~26331 specific event. This event information could be stored together with a ti~e and date ~;tamp. ~.
In an alternate ~ho~ iment of the invention, the inhaler device would po~er~ the capability to 5 signal the patient at the times ~or which ~ts use has b~aen prescribed.. Thi ~ ~ignal c:ould be provided by means of indicator light (s), audible beep~ or ~ -tones, vibration of the unit, or some combination thereof. Timing of ~uch signals would be program~ed ~0 in accordance with ~n~rd or patient specific prescription~ for ucage.
In another alternate ~nbodiD~ent of the inven-tion, the inhaler device would be integrated with a holding cha~ber (reservoir) ~nto which the aerosol i~ releaeed prior to inhalation. The interior volume of thi8 chamber would be large ~no~ to allow for the eYp~n~ion of the aero~ol. Electronic functions remain ~he same as those provided in the nsn-chamber device.

2 0 RRT~ ~ C~TpTTQN OF DRAWTNGS
Figure 1 i8 an oblique side vi~w of the p~-ent intellig@nt inhaler device.
Figure 2A i8 a side ~ectional view of the r~Ch~i cal construction of the device illustrating major components including the incorporation of the type of pressurized canister most widely used for dispensing metered do~es o~ aerosols.
Figurè 2B i~ a ~ectional view of an alternate mech~n;cal construction inco.~Glating a Venturi-type flo~ meter.

WO ~3/12823 PCI~/USg2/10804 21~6331 Figura 3 illustrates typical me~ ages and graphic oul_~ul, ~upplied to the patient or att~n~nt by the device.
Figure 4 is a bloclc diagram of electronics illustrating the overall architectur~ of the intelligent inhaler device ~igures 5A through 5E show the circuit diagrams for subsyste~ns of the device.
Figures 6~ and 6B are f low chart~; ~howing the overall pro~ef~eC for use of the intelligent inhaler by healthcare profes~ional and patient.

n~T~T~.~n r~ }2TpTToN
The overall ~oce58 of the pres~nt intelligent inhaler ~ystem i8 shown in Figure 6A which pro~.rides an overview of the protocol for closing the thera-peutic loop. ~he target profile envQlope i~
~elected and ins~ d te q., via a clinical computer-hAr~1 woLJ~sl~ation) ~ Th~ targ~t envelope is ~a) a generic patt~rn, or tb) a tailored time : 20 cour~e b~ on ~he patient'~ ind~idual Epirometric values or other input, ~s appropriate. The device is used by the patient and at the next vi~it to the phyRician's office, thQ utilization data are extracted and transferred to the clinical work-station where th~y are revi~wad by the phy~ician or other healthcare professional including analysis of ~ s with respect to pre~ious periods. T~e prescription is adju~tQd if and as appropriate and, if nc:~r-~ry, a new target profile for the given patient and medication is loaded into the int~
gent inhaler device.

WO93~12823 PCT/US92/10804 f Figure 6B i8 an overview of the proce~s for utilization by tha patient. Initially, the devi~e reminds the patient ~hat it is time to take the medication. Thi~ is used $or ~dicatio~, such afi cortico~teroids, which are taken o~er long periods of time rather than in an immediate reaction to an ~cute event ~uch a~ an asth~atic episode. The device is then turned on and the relea~e of aerosol triggered.
Recording of data b~gin~ at the ~tart o~
in~piration or upon actuation of the ~edication canister, whichever i~ earlie~t.
The actual ti~e cour~e of each inhalation i8 compared to the objecti~e target ti~e course, a co~pari~on derived, and a signal given a~ to succes~
or failure. At the end of inhalation, a timer i5 started which run~ for the period of time during which the patient ~hould hold his or her brQath. At the end of ten -o~n~C (or o~her period as ~peci-fied), an auditory and/or visual ~ignal i~ supplied to the patient. The patient can y~e~ a button to signal then breath holding ~ctually ended. In an alternate embodiment, he patient can ~ignal that event ~y exhaling (at least initially) back into the 2s hand-held d~vice with the t$me recorded when an increase in air flow abOVQ a sp~cified threshold is detected.
In addition, sugge~tions for corrective action (e.g., hold breath for a longer time) can be given.
Recorded data are stored for later readout into a record-keeping device (such as a computer-based clinical workstation in a physician's office) for 3 PCT/US92/~0804 interpr2tation and perhap~ compar~son to other time periods by a healthcare professional. ;;
An external view of the preferred phy~i~ale~bodiment i8 ~hown in Figure 1. Located in the housing 100, is a pressurized ~2d~cation cani~ter 102. An important feature i8 the ability to insert and utilize st~Ard metered-do~e inhaler canister~, although the device can be modi~ied to support other con~ners as appropriate. Communication with the patient occurs with input through push-button witch mean~ 104, and o~uL through ~ED indicators 106 and LCD panel display 108. Communication to and from the clinical workstation in the office of the physician .i~ through input/o~L~ data co~un~ation mean. 221 3 ~hown in Figure 2. While thi8 i ~hown as a ~imple 1/0 data ~ .ector ~cket in Figure 1, the invention i not 80 limited. The data communi-cation mean~ 221 in Figure 2A alBo i8 ~n~e~ to include a compact tr~n~c~~ver ~ean~ for communi-2~ cating with a spatially r~ota conLLDl ~ource, ~uch as a workstation, through a radiofreyuency communi-cation ch~nn6l, or the like in accor~nc~ with well known ter~nique~. The remote WG~ ~Lation is capable o~ receiving transmission of data such as the time o~ actual usage or the ~nhalation pattern. The present device iB also c~rahle of being reprogrammed by the remote work~tation to alter the do~age or to provide specific fe~hack to the patiQnt a8 to corrective action.
Air to be mixed with tha aerosoliz8d medication - enters from the ~r~ni n~ in the top of the inhalar hou~ing 112, and the patient's inspiration pulls the air and aero~ol mixture through mou~hpiece .114.

WO93/12823 PCT/U~92/10804 ~,;
2l~3~l A mechanical construction diagram of a preferred e~bodiment of the device is ~hown in Figure 2A. The "on" ~witch 104 for the dev~ce turn~
on the power in the battery 205 (which i8 phyBiCally A~c~cfiible through cover 207) for circuit. which are not active between times of inhaler usage. Other circuits ~ay be powered at predetermined time~, and power i~ supplied continuously to circuits re~o~ible for main~ ing the cont~nts of ~emory.
The Application SpQci~ic IntQgrat~d Circu~t (ASIC) 220 contains the microp~o.~ or, memory, calendar/-clock, power controller, LED/~ound driver, LCD
driver, input/o~uL interface, button-~witch inter- :
face, and analog to digital con~erter~ ~he elec-tronics are co~n~ctable to a work~t~tion by a con~entional ~o~ector means 221. Whether ~he device has been ~hA~en properly i8 determined by input from ~otion e~n-?r 222. Flow i~ measur~d ut~lizing a flow measuring mean~ or flow meter (com~ri~ed of~elements 232, 230, 234 and 112) as follow~. Differential prQ~sure i~ ~ea~ured through ~rt~ re ~en~or ~i~phragm 230 which i~ connected by flow rh~nn~ls 232 to both outside atmo~ph~re and interior ~low chamber 234. Pre~ e ~nsor dia-phragm 230 is connected to the pres~u~e -~nrQr elec-tronics 240 which arç interfaced to an analog to digital converter on ASIC 220. A~rosolized medica~ent is releas~d when the medication cani~ter 102 is de~ e~ and its valve 203 is open~d with the p~e~ ized liquid being ~r~h~rged through the atomizer 242. An actuation pres~ure switch 244 is di~ e~ for contact with cani~ter 102 when the WO93/12~23 2126~3 I PCI/US92/10804 canis~er is depreR~ed to discharge a unit of medicine through ato~izer 242.
Figure 2B illustrates an alternatiYQ embodiment utilizinq a v~l-L~i flow meter de~ign. This 5 construction is the ~ame as in Figure 2A except that the linear respon~e of pressure sen~or d~aphragm 230 is proportional to ~low through the Venturi-flow meter 250, with the signal transmitted by the pre~sure ~en~or electronics 240. Thi~ implementa-lO tion provides the ab~ lity for the patient to exhale~at least initially) into the device to indi~ate he end of the breath-holding period. The exhalation would be into he input port 112 to avoid cloggirlg the atomizer 242 . Th~ 8 por_ 112 could be u ed for 15 recording the patient'~ maximal e2~alation or other ~piroD~et~ic D~easurementfi. The form of p.~ re ~en~or is not cr$tical. A ~ onAt~ctor pres~ure sen~or might be directly "incorporated into an ASIC
device ~wise, K.D., and K. Na~afi, ~Micro~abrication Technigue6 for Integrated SQn~ors and Ni~G_y~Lems~
Science, 254:13351342, (1991~]. Alternatively, a d~fferent mean~ for ~easuring air flow ~uch a6 a miniaturized ma~ flow sen~or, could be Qmployed~
Figure 3 ~hows a ~et of ~ample mQssages to the pati~n~. F~h~k regarding indiv~A~ inhal~tion effort~ appears in the left column, including an illustration of the ti~e cour~e of inspiration rela-tive to a target rang~. GenQral instructions are - ~hown in the center, and prompts for event recordin~-are shown on the right. ~heRQ me~sag~s are displayed by the LCD panel 108 as shown in Figure 1.
Auditory ouL~hL comes through the Piezo sound generator 260 as ~hown in Figure 2A and 2B.

W093/12823 PCT/US9~tlO804 f Figure 4 shows a block diagram of the sy~tem.In a preferxed embodiment, many of the electronic elements are incorporat~d within application spQcific integrated circuit (ASIC) 220, including the micropro~s~r, RAM and RO~ ~torage, calendar/-clo~k, A/D converter, 1~0 function~, and drivers for LCD, sound, and LED deYic~6~ However, in variou~
imple~entations of ~he invention these function may be di~tributed on ~ultiple integrat~d circuits, including ~t~n~Ard and/or custo~ devices. The ~cope of the invention is not limited to any ~ingle ~pecific imple~entation.
The micropL-_P-~Qr m¢~ory requir~ment ~re ~upplied by the R~nAo~-Açç~r~ ~mory (RAM) and the Read-Only Memory (ROM) ~odule~. The calendar/clock ~dule provide~ the ability to signal to the patient when it i~ time to t~ke the medication, ~nd g~ner-ate~ time and date st~mp~ for ~ch inhaler use. The analog input signal from the p~e7~ e ~n~r elec-tronics is trans~ormed by the analog to digitalconverter. The power controller provides power to all the device sub~ystems including the m~cro-pL O~ or and associated co~ponents, flow-measuring circuit, LED/Qound display and driver, ind the LCD
alphanumeric p~nel and dxiver. Input/ouL~uL
Gircuitry handle~ signals coming into and/or going out o~ the pu~h-button contact ~witches and two-way communications with the computer-h~re~ clinical workstation or other suitable device occurs through the external communications conn~ctor 221.
Figures 5A through 5B illustrate subsystem circuit diagrams. Figure 5A shows the power CO11~LO1 circuit. Mcdules such as the PAM are powered W093/12~23 PCT/US9~/~0~04 continually. As to power control, when the motion sen~or 500 is triggered with transmission ~hrough the MOSFET semiconductor 502 on the left or the "on"
504 button switch closed, the NAND 508a, 508b gate change state and ~witch on the NOSFET ~emi~n~ctor 510 on the right to provide voltage to the micro-pror~C~or. ~hen the microprocessor goes into the ~'sleep mode" after its opexational sequenc~, it trans~its an l-of f '~ ~ignal to the ~OSFET 8emi-conAl~ctor 512 which deactivates the NAND gates 508a, 508b and shuts the system down. The device i8 battery operated using preferably a lithium battery ~or long life.
Figure 5B shows the p~ e -~Pror flow~eter electronic~. The strain gauqe re~istor~ 520a, 520b, 520c and 52Od in the bridge circuit are located on the pxessure-sensor ~i~p~ragm 230 which ~easures the pres~ure differential in the flow m~ter co~prised of el~ents 232, 230, 234 and 112 in Figure 2A or in the ~llLuL~ flow ~ter 2S0 Bhown in Figure 2B. In accor~nce with te~hniquçs which are well known to those ~killed in the art, an analog ~ignal i~
generated through the two stages of operational amplifiers 522, 524. This signal i8 tran~formed by the analog-to-digital converter 530 and fed via a bus to the micropt~ or (not ~hown).
Figure 5C illustrates ~he LED/~o~ln~ display and driver. The control signal comes from the micro-~oc~--or to 8 bit latch 540. The ~G..L~ol signal is ~tored by the 8-bit latch 540. Selected components, such as zero to six of the L~D~ 542 and zero to two Piezo -o~ generators 544 are turned on. In like manner, co~ponents which are on can be turned off ~ , . ~

WO93~12B23 PCT~US~2/108~
~, Zl?~633~

wlth a subsequent control signal tran~tt~d by the mlcroproo~or .
Figure 5D presents the block diagram for th~
LCD alrhAn~eric panel and driver. The eo..L~ol signal comes in over ~he bu~ to the microprooQ~sor and the LCD controller provide~ input to ~he LCD
dri~er (input to rows of display) and the LCD dot-matrix display panel (input to colu~ns of di~play) in ~ccordance with te~hnique which ~re well known.
Figure 5E illu8tr~te8 the pu.h-button switch interface. Becau~e ~hi~ interface r~id~s on the microprsç~cr bu~, a three state buffer i8 u8ed (off, flo~ting, on). In the fi~ure, the ter~
tri~tate is used, reflecting a particular version of the buffer pro~l~cQ~ by National Semiconductor Corpo-ration. The current status of each of the pu~h-button switches i8 held within the bu~fer. The thLee _tate buffer is interrogatQd by the mic~o-~ G. --~or by turning the thre~ ~tatQ control to "on"
and th~ statu o~ ~ach line (~on~ or ~o~f~
tran~mitted from the three-state bu~f~r back to the mio~G~ooe~or over the micropro~ or bu~.
Figure 6A -~hows the overall protocol whereby data collected by the intelligent inhaler are used to close the therapeutic loop, and enable the healthcare pro~ider to track the patient's ~edica-tion u~e between visits. The physician ~lects the target profile for the patient and medication. The profile is loaded into the device and the device is u~ed by the patient. At the next ~isit of the patient to the healthcare provider, the data related to pati~nt utilization o~ the device is extracted and ~o~ed to the clinical workstation. rhe data are wos3~12823 2 ~ 2 6 3 3 1 PCT/US92/108~

-- 19 -- , ., then reviewed by the physician and trend analysis can be don~, not only within the given ~et of data, but in co~parison to pre~iou~ period~. An ad~u~t-ment ean be made to the prescription ~f the physician ~hoQ~e~ to do 50. If ~here i8 a change, the new prescription infor~ation and/or target profile are loaded into the intelligent inhaler device.
Figure 6B illustrates the pr~eF~ of utiliza-tion of the intelligent inhalation device by the patient. If the medication i~ tak~n at pre~cribed interYals rather than on an epicodic basis, a :.
remin~r of the time to take the medicine iB
sig~Alted to the patient. ~he patient depr~e~ the "on" ~witch to indicate the med~cating ~equence i~
to be st~rted and chA~ the device with the cani~ter in~erted 80 the mQdication i8 ad~quat~ly prepared for ~;~ch~rg~. DepreR~ion of the cani~ter ~ Y~h to Air~h~rge the m~dication i~ the trigger event. Recording of the data, including rQlea~e of aero~ol, airflow time cour~e, and ~roriated time and data StampB e~ r. DQri~ed valU~8 ar~ calcu-lated and compared to the target ~alue~ of the target function. The breath holding period is timed and an auditory and/or vi~ual ~ign~l ~upplied to the patient at its end. .Auditory and/or vi~ual f~dback i~ provided to the patiQnt a~ to ~ucce~ or failure of the inhalation actions including text ~o~sagas a~
to what correction~ ar~ a~o~ iate (e.a., T~U~
SLOWER). At the n~xt patient v~sit, the l~_ur~ad data are read into the hoEt clinic~l workst~tion and the d~ta analyzed and displayQd, Lncluding trend analysi~ in compari~on to pr~vious periods.

WO93/12823 PCT/U~92/10~04 2 ~6~ 3 ~ - 20 -A typical cycle of operation, with reference to Figures 1, 2A and 2B, is a~ follow~:
If the medication i8 to be taken regularly, the ti~e for the med~cation to be takan c~n be ~ignalled through Piezo sound generator 260 and/or LED di~play 108.
The unit is held in patient's hand such ~hat mouthpiece 114 faces the patient.
The patient pres es push-button ~witch 104, activating the "on" switch to clo~e and activate thle microproc~or and associated functions.
The patient r~A~e~ the unit per in~tructions, causing the motion ~e~or 222 to gonerate a signal for storage in the ~e~ory contained in the ASIC ~20.
If the on ~witch 104 ha not y~t been activated, motion sensor 222 causes the unit to turn on jU8t as if the on had b2en closed. Optionally, thi~ signal al o prompts indicator lights 106 to turn on a8 well.
Patient then places the ~outhpiece 114 in ~outh, depres~ec ~edication canister 102 firmly enough to cau~ ~etering ~ech~n~ 03 to ~;rch~rge a unit of medicine through atomizer 242, and the patient simultaneously begins to inhale. Depress$on of tha canister 102 causes closure of actuation sensing switch 244 and tran~ission of a signal for this event t~ microprocessor within the control electronics of ~SIC 220.
Nith the inhalation, aerosolized medication flow~ through the mouthpiQce 114 into the mouth of the patient.
Pra~u~ n~or ~r~ragm 230 e~ air flow coming through the upper housing opening 112 and wos3/l2823 PCT/US92/10804 mo~ing through flow chamber 234 by measuring the pres~ure differential between the outside air ~hrough passage 232 and the ~nternal chamber 234 (in the configuration shown in Fig. 2A). In the alt~r-nate construction shown in Figure 28, pre~sure sensor diaphragm Z30 senses air flow by measuring the pre sure differential between ~he two ~tage~ of Venturi flow meter 250. Pre ~ure-sensor electronics 240 generate~ a signal repl~eçntative of flow rate to the analog-to-digital con~erter contained in the ASIC 220.
The analog-to-digital circuitry converts thi~
signal to digital form, upon whi~h it i~ ~tored a~ a series of (e~g., 8-bit) sa~ples in a RA~ con~in~
in ~he ASIC 220.
As patient contin~s to in~pire, time ~erie~
flow samples in memory are compared with target objective profile representative of correct inhala- -tion technique al~o stored in ~AM contA~n~~ in ASIC
220. The microp~ r cont~;n6~ in ASIC 220 performs the compari~on of actual versus target value6 and depen~inq upon the result~ ~and~ stgnal~
to indicator LED's 106.
Upon completion of in~piration, ~sration of flow ie detected and measurement of time duration of breath hold beqins using the cal~ndar/clock module cont~in~ in ASIC 220.
Upon end o~ braath hold, patient p.f-~e~ pu~h button 104 which ~nA~ an evont ~ignal to micro-p~ or in ASIC 220 for ~torage in PAM and calcu-lation of breath-holding duration.
Re~t lts of the maneuver, incl~ ng breath holding performance are used to select textual or WO93/12823 PCT/~S~2/10804 ., ~ .

2 ~2 63~ ~ - 2~ -iconic feedback from a table stored in RAM contained in ASIC 220, in accordance with tec~ique~ which are well known for di~play to patient via LCD di~play s panel 108~ Note that text table c~n con ist of ~ultiple sections corresponding to differi~g la~guages.
After ~he inhalation m~neuver is complete, the device can pose questions to the patient on LCD
display 108 and answers such as "yes" or "no", or other answers corresron~ to the numb~r of ti~es the push button switch is activ2ted are input by the patient through pu h-button ~witoh 104.
A~ter a specifi~d time (long enough to per~it an additional ~ Arge of ~edication if there i~ to be on~) an o~y~L ~ignal from the mi~lo~ e_-or to the power ~o-,L~ol circuit cau~es the ~ystem to e~r 11 to sleep mode.
Data ~ro~ multiple maneuvers can b~ downloaded c~h~uently through ronn~ctor 221 into a clinical workctation or similar device for review by profes-sional including trend analysis within the se~ of ju~t downloaded data and comparison to previous period~.
Upon downlo~ g of data, records for individual maneuver~ are erased from the RA~
con~ne~in ~SIC 220, and battery 205 i8 checked for charge.
The site of compliance monitoring includQs a digital computer means (not shown) for communicating electronically with the microproce~-or ~eans 220 incorporated in the programmable inhaler~ The digital computer means at the monitoring site includes means for monitoring and i~oving a WO93/12823 2 1 2 6 3 3 1 PCT/U~92/108W

- 23 - ;

patient's medication compliance with the use o~ the hand-held i~haler~ The monitoring computer i8 lin~e~ with transmission ~ans for re~ote electronic retrieval of the data mea~ured by and storQd in the inhaler mi~Lo~oce~ror through data communication te~hn~gues which are well known, such as radio-freguency, optoelectronic communication, or the like. ', The monitoring computer is ~v~am~ed to evaluate the data received from the inhaler ~icro-proc~ror ~eane and to provide interpretations of the effectîveness of compl~ance efforts based on he retrie~ed data. The monitoring computer also includes a display mean~ for ffleaning~ul display of the compliance dataO Such di~pl y means preferably includes patient's projected target envelope for maximized delivery of ~edication ~ compared to the actual, m~a~ured performance of the patient.
It will be appr~ciatQd by tho~e ~killed in the art that there are a ~ultitude of methods for progra~ming the ~onitoring co~puter to achieve the evaluation of a pati~nt'~ medication compliance parameter~ which will maxi~izQ delivary of medica-tion to the large airways, s~all airway6, alveoli or any part of the respiratory tract. Thu8, the pr~ent m~thod is not intenA~ to be limitQd to ~
specific software impl~mentation for diagnosing a patient' 5 project~d compliancQ as a target ~nvelope of values and for mea~uring th~ actual performance of the patient with re~pect to the target envQlope.
In a preferred embodiment, the monitoring co~puter includes software which is readily p~v~Lammed by one skilled in the art to utilize data WO93/12823 PCT/US92/~0804 2~633~

input from diagnostic in~truments, diagno t~c tests, clinical records, clinical ob~ervation~, profes-sional opinions~ or the like in calculating a target envelope of inhalation para~eters which will ~axi-mize the delivery of aerosoliz~d medication to anyselected par~(.) of the re~piratory tr~ct of a particular patiant, or to indic~te o~her change~ in therapy such a~ type o~ medic~tion. The for~going data include quantifiable par~meters relating to thf~
physical condition of the airw~ys of a patient, such as the size of the patient'~ air p~s~age~.
The data are input into the ~onitoring computer as a table of value , or phy~ical para~eters indica tive of the condition and cArAr-lty of a patie~t's ~S air r~ eways and inhalation characteri~t~c~. The table of physical parameters are then ~apped to pxovide the target envelope of values, which if matched by the pat~ent's performancs, will m~xi~ize the distribution of the aero~ol mQdicat~on any selected parts of the respiratory tract. The moni-toring computer compares the patient's actual measured performance to the target envelope. The monitoring co~puter then communicates electronically with the mic~G~ or in the inhaler, ind a8 a func~ion of ~easured compliA~c~ par~meters, ~ o grams the microproc~or, ~f nec~Q~-~y, with differ-ent target inhalation profilQs, dosage 1eVQ1g or actuation event ti~es that will bring the pationt's performance within the target envelope and maximize ~he therapeUtiC '~r~
The advantages of the system dascribed herein over convantional devices may be sum~arized as ~ollows:

wos3/l28~ PCT/US92/10804 ~;
212S33~

(a~ the incorporation o~ both ~onitoring and '.
recording the patient's inhalation time cour e and related e~ents in a medicine inhaler device ~all and aesthetically pleasing eno~ to be u~ed during normal day-to-day activitie6, (b) the ability to load in a target perfor-mance en~elope for one or more inhalation ti~e/value csur es and/or one or ~ore ~elected variables (~uch as peak-flow rate) or to de ignate a 3peci~ied generic curve, (c) the ability to -~nre whether the device ha~ been c~ken properly prior to ~irc~Arge of a dose of aero~oi, (d) the ability to provid~ ediate f~e~ck both during the inhalation and ~fterwards a~ to where the patient' 8 performance fit~ relative to the target-perfor~nce envelop~ and whether and whan inhalation values fell outside that envelope, (a) the ability to pr~vide f~Q~haçk to the patient as to what co~ tive ~ction, ~f any, ~hould be taken, (f) the ~bility to provide a signal to the patient prompting him or her to continue breath holding, (g) the ~bility to ha~e the patient record the ti~ing of the end of the br~ath-holding period, (h) the ~bility to store any of tha data ~
ob~ne~, i (i~ the ability to download longi~ n~l results from the Intelligent Inhaler into a health-care ~ L~t~on or similar device, and (~) the ability for th~ healthcare profes-sional to review a patient's medicine usage for the ~,~?,63 ~

entire period between office visit~, and therefore revi~w trend~ in the patient's conditlon in the context of a detailed hi~torical record of the actual delivery of medication to its target ~ites of action in the lungsO
It ~hould be ~oted that all of the above capa-bilities wQuld not nece~fi~r~ly be included in every implementation of the 5y5te~.
The device and method described here are not limited to usage with any one pharmaceutical. They may be used with locally acting respiratory drug~
including bronchodilators, corticosteroids, anticho-linergics, antibiotics, and others, as well a~ with systemically acting drugs. Differing com~o~.~ may require v2riation in prescribed usage, including change6 în the inspiratory flow pattern. Such patterns may be oho~en in order to direct the roncentration of drug deposition at di~fer~nt sites within ~he respiratory tract, or compen~ate for varia_ions in patient'~ airways ~orphology due to di3e~-e or trau~a.

Claims (10)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A hand-held, portable inhaler device, comprising;
a delivery means, which upon actuation, releases a meter dose of aerosolized medication from an associated pressurized canister;
an electronic sensor means for continuous measurement of air flow through a channel;
a mouthpiece leading to the channel which leads to the delivery means;
a means for storage of data including relative time of actuation of the delivery means, and data representative of duration of inspiration through the channel;
a means for performing logical operations or interpretive calculations on the data; and a motion sensor means for detecting if the associated canister has been shaken prior to actuation of the delivery means.

2. The device of Claim 1, further comprising;
a signaling means, responsive to the means for performing, for providing feedback to a user, wherein the feedback expresses to a user whether the delivery means has been used correctly.

3. The device of Claim 2, wherein the signaling means for signaling to a user a scheduled time for activating the delivery means.

4. The device of Claim 1, further comprising;
a means associated with the means for storage of data for retaining recorded data from multiple delivery activation events; and a means for later retrieval of the data for review by a healthcare professional.

5. A device according to Claim 2, wherein a target envelope pattern representing the time course of an effective inspiration is stored in the storage means for comparison to actual inspiration patterns, whereby such comparison is used to govern feedback supplied.

6. A device according to Claim 2, wherein feedback to the user includes specific advice in the form of textual messages and/or labeled indicator lights as to the type of corrective action necessary for effective use of device.

7. A device according to Claim 1, wherein the means for performing logical operations further comprises a means for recording timing of the end of a post-inspiratory breathhold period.

8. A device according to Claim 1, wherein the mouthpiece is connected to the device such that rotation or removal of the mouthpiece turns the device on or off electrically.

9. The device of Claim 1, wherein the mouthpiece comprises a cover which upon rotation or removal activates the electronic functions.

10. A hand-held, portable inhaler device, comprising;
a delivery means, which upon actuation, releases a meter dose of aerosolized medication from an associated pressurized canister;
an electronic sensor means for continuous measurement of air flow through a channel;
a mouthpiece leading to the channel which leads to the delivery mechanism, the mouthpiece being connected to the device in a manner such that movement of the mouthpiece by the user results in electronically turning the device on or off;
a means for storage of data including relative time of actuation of the delivery means, and data representative of duration of inspiration through the channel; and a means for performing logical operations or interpretive calculations on the data.