SUMMARY OF THE INVENTION In accordance with an aspect of the invention, there is provided a drug delivery device for administering a drug contained in an aerosol to an oronasal passage which comprises

(a) a collapsible airbag of fixed maximum dimen¬ sions which is impervious to passage of air except for an airbag opening, said airbag having a first apertured end cap, presenting said airbag opening, and a second end cap facing said first apertured end cap, said two end caps being joined by a collapsible mater¬ ial so that as said airbag collapses and the end caps move together, said end caps rotate in relation to each other;

(b) a piece having one end communicating with said oronasal passage and connected by a bidirectional channel through said piece to the opposite end thereof to said airbag opening, said piece having a drug introduction opening for the introduction of a spray containing a drug, said drug introduction

directly into said airbag through said piece and said airbag opening, in a direction away from said one end; and said drug delivery device admitting a drug-containing aerosol through said drug introduction opening while said collapsible airbag is at least partially expanded, said drug being introduced into said oronasal passage with the contraction of said collapsible airbag.

Also in accordance with an aspect of the invention there is provided a method of treating a patient suffering a disease in the tracheobronchial tree which comprises administering to the tracheobronchial tree a drug selected from the group consisting of 6alpha-flouro-llbeta,16alpha,17,21-tetrahydroxypregna-l, 4-diene-3,20-dione cyclic 16,17-acetal, 5-[l-hydroxy-2- [ (1-methylethyl)a ino]ethyl]-benzene diol and 4-hydroxy- 3-hydroxymethyl-alpha-[ (tert-butylamino)-methyl]benzyl alcohol in an amount of effective to treat said disease, said method comprising the introduction of- said compound as an aerosol spray into an expanded airbag having means for communicating said compound with an oronasal passage of said patient, said airbag being otherwise substan¬ tially impervious to the passage of air, and thereafter collapsing said airbag with said means for communicating said drug with the oronasal passage in position to deliver said drug thereto, and whereby a metered dose of said drug is delivered to said tracheobronchial tree to relieve said disease and entry into the gastrointestinal tract is avoided.

While treatments via metered dose inhaler effect bronchodilatation in patients with airways obstruction, 5-[l-hydroxy-2-[ (1-methylethyl)amino]ethyl]-benzene diol delivered by the invention produced greater bronchodila- tion compared to 5-[l-hydroxy-2-[ (1-methylethyl)amino] ethyl]-benzene diol or 4-hydroxy-3-hydroxymethyl-alpha- [ (tert-butylamino)methyl]benzyl delivered by the conven-

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tional metered dose inhaler. The increase in SGaw, with 5-[l-hydroxy-2-[ (1-methylethyl)amino]ethyl]-benzene diol in accordance with the invention over the other treatments was considerable at all times and unlike the conventional metered dose inhaler was* ^' still well maintained two hours after its administration. One puff of 5-[l-hydroxy-2-[ (1-methylethyl)amino]ethyl]-benzene diol or other bronchodilator administered every two hours with the invention may be a more efficacious means of achieving bronchodilation during symptomatic bronchospasm than the advocated usual dose of two puffs every 4 to 6 hours via the conventional metered dose inhaler.

Signal means are preferrably provided in said bidirectional channel to indicate when the rate of passage of said drug exceeds a desirable limit, whereby the patient-taking said drug is reminded to decrease the rate of collapse of said airbag, thereby maximizing drug utilization. The said drug delivery device admits a drug-containing aerosol through the drug introduction opening while the collapsible airbag is at least partially expanded, the drug being introduced into said oronasal passage with the contraction of said collap¬ sible airbag. The signal means provided may be a whistle activated by passage of air from said airbag into said bidirectional channel at a rate in excess of the desirable limit for effective drug utilization, particularly a reed whistle device. The piece is a tube for communication with the mouth, whereby said drug is delivered to the tracheobronchial tree. The collapsible bag advantageously has a first apertured end cap having said airbag opening and a second end cap facing said first apertured end cap, the two end caps being connected by a collapsible material. The collapsible material is advantageously attached to the two end caps so that as said airbag collapses, the facing end caps rotate in relation to each other.

In a further embodiment, the piece is a mask shaped for communication with the nose, whereby said drug is delivered to the nasal mucous membranes. The signal means being a preferred embodiment, the invention thus more broadly is directed to a drug delivery device for administering a drug contained in an aerosol to an oronasal passage which comprises a piece having one end communicating with said oronasal passage and connected by a bidirectional channel through the opposite end of said piece to an airbag opening, said piece having a drug introduction opening for the introduction of a spray containing a drug, said drug introduction opening disposed such that said drug is introduced directly into said airbag through said piece and said airbag opening in a direction away from said one end; and a collapsible airbag of fixed maximum dimensions which is impervious to passage of air except for communication with said airbag opening, said drug delivery device admitting a drug-containing aerosol through said drug introduction opening while said collapsible airbag is at least partially expanded, said drug being introduced into said oronasal passage with the contraction of said collapsible airbag.

An airbag (sometimes hereinafter also termed an inflatable envelope) , is provided for receiving a measured quantity of aerosolized drug (also sometimes referred to herein as medicant) . The airbag or envelope has interior surfaces which confine the received drug or medicant and an opening for delivering the drug or medicant to a patient. A piece is provided in communication with the opening for conducting to the patient's mouth or nose the drug in the airbag which becomes mixed with a predetermined amount of air. The patient evacuates the airbag by applying a negative pressure to the mouthpiece. Means are provided on the interior surface of the envelope to maintain them apart, thereby preventing collapse of the envelope. In a

preferred embodiment of the apparatus according to the invention, medicant is discharged into the envelope through a small nebulizer connected to a pressurized inhaler bottle. When a predetermined quantity of aerosol and medicant is discharged from the bottle, the discharged stream is directed into the envelope. The envelope is connected to a mouthpiece serially connected with the nebulizer. The resulting structure permits the medicant to enter the envelope in a first direction, and upon the application of a negative pressure to the mouthpiece by the patient, the contents of the envelope are delivered in a second direction which is opposite to the inflating direction and thus to the patient's pulmonary tissue. By first filling the envelope with the aerosolized medicant, and then withdrawing the contents of the envelope into the patient's respiratory system, controlled inhalation of the medicant results, improving the rate and distribution of the medication in the respiratory tracts.

DESCRIPTION OF THE DRAWINGS Figure 1 is a cutaway, partial cross sectional view of another embodiment of the invention as used for oral inhalation.

Figure 2 is a cutaway, partial cross sectional view of the embodiment of the invention as shown in Figure 1, but modified for use for the nasal delivery of drugs.

Figure 3 is a partial cutaway view of another embodiment of the nebulizer assembly and mouthpiece of Figure 1.

Figure 4 shows a disc employed in the invention of Figure 3.

Figure 5 shows a screen employed in the invention of Figure 3.

DETAILED DESCRIPTION OF THE INVENTION 5-[l-Hydroxy-2-[ (1-methylethyl) amino]ethyl]-1,3-benzene diol in the form of its sulfate is a widely used brochodilator (metaproterenol, Alupent, Metaprel,

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Alotec, Novasmasoi) . Another drug in this same general category is 4-hydroxy-3-hydroxymethyl-alpha- [ (tert-butylamino)methyl]benzyl alcohol, 4-hydroxy-3- hydroxymethyl-alpha-[(tert-butylamino)methyl]benzyl alcohol (Aerolin, Broncovaleas , Sultano ^' l, Ventlin, Ventolin, Proventil) . In accordance with the traditional modes of application, the manufacturer of 5-[l-hydroxy-2-[(1-methylethyl)amino]ethyl]-benzene diol recommends a metered dose inhaler having 225 mg micronized powder in an inert propellant, which has approximately 300 doses. The drug is contained in a 15 ml inhaler which fits into a mouthpiece for administration of the drug. Two to three "puffs" of inhalant is a usual dosage, repetitive dosing to be taken not more than about every three to four hours, with a total dosage per day maximum of about 12 such "puffs" of inhalant. According to Facts and Comparisons, p. 586 (1980), deaths have been reported following excessive use of inhalation preparations, it being stated that the exact cause is unknown, with car¬ diac arrest having been noted in several instances. It is also stated that in patients with status asthmaticus and abnormal blood gas tensions, improvement in vital capacity and in blood gas tensions may not accompany an apparent relief in bronchospasm. Also reported for 5-[l-hydroxy-2-[ (1-methylethyl)amino]ethyl]-benzene diol is the observation that in occassional patients, a severe paradoxical airway resistance takes place with repeated, excessive use of inhalation preparations. It is reported for 4-hydroxy-3-hydroxy- ethyl-alpha-[(tert-butylamino)methyl]benzyl alcohol [Physician's Desk Reference, p. 662 (1981)] that excessive use of adrenergic aerosols is potentially dangerous. Fatalities have been reported following excessive use of Alupent metered dose inhaler, brand of metaproterenol sulfate, as with other sympathomimetic inhalation preparations. It is particularly noted in

this PDR reference that "[e]xtreme care must be exer¬ cised with respect to the administration of .additional sympathomimetic agents. A sufficient interval of time should elapse prior to administration .of another sympathomimetic agent. *** [I]t should be used with great caution in patients with hypertension, coronary artery disease, congestive heart failure, hyper- thyroidism and diabetes, or when there is sensitivity to sympathomimetic amines." In addition, it should be particularly appreciated that with the traditional "puff" of aerosol such as is commonly used with drugs such as 5- [l-hydroxy-2- [ (1-methylethyl) amino] ethyl] - benzene diol or 4-hydroxy-3-hydroxymethyl-alpha-[ (tert- butylamino)methyl]benzyl alcohol the quick administra¬ tion of the drug into the mouth is not accompanied by a sudden uptake of air into the patient' s lungs that would take advantage of the aerosol's action to substantially deliver the drug into the patient' s tracheobronchial tree, much of the drug instead not going into this desired area, but being delivered into the gastro¬ intestinal tract, the very antithesis of the administration of an aerosol drug such as 5-[l-hydroxy-2-[ (1-methylethyl) amino]ethyl] -benzene diol that is designed for delivery into the tracheobronchial tree. This problem is implicitly recognized in the Proventil (Schering) "Patient's Instructions for Use" for the aeresol 4-hydroxy-3-hydroxymethy1-alpha- [ (tert- butylamino)methyl]benzyl alcohol preparation, which includes the following instructions:

2. BREATHE OUT FULLY, expelling as much air from your lungs as possible. ***

3. WHILE BREATHING IN DEEPLY, FULLY DEPRESS THE TOP OF THE METAL CANNISTER ****

4. HOLD YOUR BREATH AS LONG AS POSSIBLE. ***

In other words, the traditional "puff" of aerosol medication is recognized as being not completely r-

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satisfactory by the experts themselves, who attempt to have as much of the drug reach the tracheobronchial tree as possible by having the patient breath in very deeply at the very time he administers the puff of aerosol, and then have the patient hold his breath for as long as possible. It is not surprising that this is a difficult procedure to follow, in accord with the published findings of Gayrard et al, supra, that only little more than a quarter of the patients observed in his study even followed this type of instruction.

Another drug that has been administered through inhalation is 9-chloro-llbeta,17,21-trihydroxy-16beta- methyl-pregna-1,4-diene-3-,20-dione 17,21-dipropionate, beclomethasone dipropionate [Beclovent (Glaxo) ] , which is dispensed from a similar inhaler as a metered-dose "puff" which contains a microcrystalline suspension of 9-chloro-llbeta,17,21-trihydroxy-16beta-methyl-pregna- l,4-diene-3-,20-dione 17,21-dipropionate trichloromonofluoromethane clathrate in a mixture of trichloro onofluoromethane and dichlorodifluoromethane propellants in oleic acid. Each actuation delivers a "puff" of 42 meg of 9-chloro-llbeta,17,21-trihy- droxy-16beta-methyl-pregna-l,4-diene-3-,20-dione 17,21-dipropionate, providing about 200 oral "puffs".

In accordance with a further aspect of the invention there is provided as the oronasal route the selection of the nasal administration of drugs. This route of administration is indicated where a localized administration of the drug to contact the nasal passages is indicated for relief in that area with drugs such as phenylehprhine hydrochloride (Neo-Synephrine, Winthrop) or oxymetazoline hydrochloride (Afrin, Schering) , as well as situations where systemic uptake of a drug through the nasal mucous tissues is indicated to avoid the problems often associated with oral administration of drugs. For example, whereas scopolamine is an effective motion sickness drug the pass through the

liver makes this mode of administration unsatisfactory, passage through the nasal mucous membrane avoiding a first pass through the liver associated with oral administration of the drug, and also providing a relatively rapid delivery of the drug superior in that regard to transdermal medication of the drug which has a delayed action versus nasal administration. The delivery of nasal decongestants is particularly indicated in accordance with the invention, with two particular advantages over the prior art inhalants. In the prior art inhalants, the drug is administered by giving a quick puff into the nose, with the result being that most of the drug hits the nasal passage at the front of the nose, only a minor amount of the drug hitting the back portion of the nasal passages. With the regular "breathing" in of the drug in accordance with the invention, it is seen that a more even passage of the drug throughout the nasal membrane area occurs. In addition, the drug that is traditionally "shot" into the nose may pass into the body, as the patient breathes in further after administration of the quick puff. In accordance with the invention, after administration of the drug, and before further, breathing by the patient, the apparatus of the invention is operated to remove the identical volume of air that had been administered, i.e., evacuating the same amount of air from the nasal passages as had been administered, thereby providing a second pass of the drug through the nasal passage as the drug is withdrawn and to eliminate all of the unabsorbed drug, so that essentially none of the drug enters the body of the patient except through the sought entry through the nasal mucous tissue.

Figure 1 employs a basic nebulizer assembly 56 with mouthpiece 19 and pressurized inhaler bottle 21. Nebulizer assembly 56 attaches to mounting portion 57 of airbag assembly 50. Airbag assembly 50 is comprised of apertured end cap 51 and end cap 52 connected together

by sidewalls 53. Apertured end cap 51, end cap 52 and sidewalls 53 form cavity 54. Apertured end cap 51 and end cap 52 may be made of commercially available plastic material. It is contemplated that walls 53.are made of 2k mil polyethylene, although they may be ^' composed of any suitably flexible and light material. Side walls 53 would be connected to apertured end cap 51 and end cap 52 by heat sealing around the peripheries 58 thereof. The design of air bag assembly 54 can be of any suitable materials such that it provides a gas impermeable, closed bag that may be attached to nebulizer assembly 56. It is particularly contemplated that the apertured end cap and the _end cap may be manufactured in such a manner that it is easily portable and may fit in the pocket of any user. When apertured end cap 51 is detached from nebulizer assembly 56 with a twisting motion, apertured end cap 51 may be rotated in relation to end cap 52 to form a flat assembly with apertured end cap 51 resting on end cap 52 and side walls 53 automatically folded up therebetween. These pieces, working in concert, provide for an easily assembled and easily used, highly effective apparatus. The device of Figure 1 has a 700 ml collapsible bag in which aerosol is injected. The bidirectional means for communication with the oronasal passage in the mouthpiece is filtered with a reed which vibrates at inspiratory flows greater than .3 L/sec to produce a noise. Patients are instructed to keep inhalation silent while breathing. One puff of 5-[l-hydroxy-2-[ (1-methylethyl)amino] thyl]- benzene diol (650 ug) administered via the device of Figure 1 (with one breath rebreathed) is compared to 1 puff each of 5-[l-hydroxy-2-[ (1-methylethyl) amino]- ethyl]-benzene diol (650 ug) and 4-hydroxy-3- hydroxymethyl-alpha-[ (tert-butylamino)methyl]benzyl (100 ug) from usual metered dose inhaler utilizing serial measurements of body plethysmography and spirometry. Respiratory inductive plethysmography

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measured point of metered dose inhaler actuation, volume of inhalation, inspiratory flow and breathholding pause. Ten patients with chronic airflow limitation due to asthma or chronic bronchitis were given typed instructions on metered dose inhaler usage ^' and trained shortly before the study.

5-[l-hydroxy-2-[ (1-methylethyl) amino]ethyl]-benzene diol via the device of Figure 1 produced significantly greater maximal increase in SG 195 ± 52% (SE) compared to 5-[l-hydroxy-2-[ (1- methylethyl)amino]ethyl]-benzene diol or 4-hydroxy-3- hydroxymethyl-alpha-[ (tert-butylamino)methyl]benzyl via conventional metered dose inhaler, 101 ± 24% and 86 ± 26%, respectively (p less than .003) . Bronchodilator response in four patients unable to coordinate actuation of the metered dose inhaler with inspiration was significantly less than in six patients with good metered dose inhaler technique (p less than .005) . The mean flow rates were 1.02 ± .29 L/sec and .54 ± .16 L/sec during inhalation of SPT and 5-[l-hydroxy-2-[ (1-methylethyl)amino]ethyl]-benzene diol, respectively, compared to .19 ± .02 L/sec and .24 ± .03 L/sec during the first and second inhalations, respectively, using the device of Figure 1. This device was well accepted by the patients and promotes more effective bronchodilation than conventional metered dose inhalers. The efficacy of the device of Figure 1 was compared using one puff of 5-[l-hydroxy-2-[ (1-methylethyl)amino]ethyl]-benzene diol to one puff of

5-[l-hydroxy-2-[ (1-methylethyl)amino]ethyl]-benzene diol and 4-hydroxy-3-hydroxymethyl-alpha-[ (tert-butylamino)- methyl]benzyl delivered by conventional metered dose inhaler in 10 patients with chronic airways obstruction. All the patient's were trained in the use of metered dose inhaler a few days before the study and their technique was non-obtrusively assessed during the trial utilizing

respiratory inductive plethysmography. Five male and five female patients with chronic airflow limitation, seven of whom had asthma, and three with chronic bronchitis were studied with the results tabulated below in Table I.

TABLE I

CHARACTERISTICS OF PATIENTS

Maximal % Increase In SGaw

PATIENT Sex Age Baseline FE -^ SGaw Clinical MDI OF THE INVENTION (Year) (L) (% PRED) (l/sec/αrl^O/l) Diagnosis PRIOR ART (Figure 1) A B B

1 M 43 1.42 38 .023 Asthma 267 200 300

2 M 76 1.65 66 .050 Asthma 100 225 160

3 F 76 1.99 124 .080 Asthma 56 71 125

4 . N 50 .77 22 .023 Asthma 33 0 267

5 M 41 3.0 80 .033 Asthma 192 161 600

6 F 61 .87 36 .046 Asthma 43 116 133

7 F 76 .90 46 .038 Asthma 15 31 103

8 F 77 .78 43 .037 Chronic 50 125 100

Bronchitis

65 .98 51 .050 Chronic 60 40 120

Bronchitis

10 M 74 .88 31 .049 Chronic 46 38 37

Bronchitis

A = 4-hydroxy-3-hydroxymethyl-alpha-[ (tert-butylamino)methyl]benzyl

The age ranged from 41 to 77 years (mean 64) . At the time of the investigation, no patient was suffering from an exacerbation of their illness. Prior to the study, all patients showed an increase in forced expiratory volume in 1 sec (FEV- of at least 15% and at least

45% increase in specific airway conductance ( ^SG _aw ) after three deep breaths of aerosolized racemic epin- ephrine or isoetharine delivered by D_ _Q generator.

The patients were requested to stop their usual metered dose inhaler for at least 9 hours and theophylline for at least 16 hours before each study day. Those taking oral corticosteroids continued on the maintenance dosage.

All subjects underwent pulmonary function testing in the seated position. Measurement* of the forced expiratory volume in one second (FEV..) and forced vital capacity were obtained with a dry rolling seal spirometer (Ohio 800, Ohio Medical Products, Houston,

Texas) . Airway resistance (Raw) and functional resi- dual capacity (FRC) were measured by body plethys¬ mography. Specific airway conductance was calculated by dividing the reciprocal of R by the thoracic gas volume at which Raw was measured. Baseline values were recorded and were repeated at 15, 30, 60 and 120 minutes after administration of bronchodilator. The mean and maximum of three measurements of body plethys¬ mography and spirometry, respectively, were used in statistical analysis.

The test involved the device of Figure 1, with the airbag in expanded form having a 9 cm diameter and a 11.5 cm length. The nozzle of a canister containing aerolized 5-[l-hydroxy-2-[ (1-methylethyl) amino]ethyl]- benzene diol was inserted into the piece. 650 ug of aerosolized 5-[l-hydroxy-2-[ (1-methylethyl)amino]ethyl]- benzene diol was injected. The patients were instructed to inflate the bag, actuate the aerosol canister, inhale from the bag until it was empty, breathhold while slowly

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counting to five, exhale back into the bag, and again inhale and breathhold while counting slowly to five. They were requested to inhale slowly in order to prevent the reed from making the sound.

The size distribution of aerosol -delivered by metered dose inhaler was measured by using a 6-stage cascade impactor (Anderson Samples Inc., Atlanta, GA) . Impaction loss of the metered dose inhaler aerosols on the surface of the oropharynx under the conditions of usual delivery mode was determined by using a glass model of the adult oropharynx which had similar dimen¬ sions to a commercial model (Laerdal Medical Corp. , Tuckahoe, NY 10707) . The metered dose inhaler was connected to the mouth of the glass model and the aero¬ sol was delivered directly into the model while 0.5 L/sec of dry air was continuously passed through the model. Aerosol particles escaping from the pharyngeal end of the model were collected on a filter and weighed. To estimate the influence of the number of breaths rebreathed in enhancing deposition of aerosol in the airways, a monodisperse aerosol of 4.0 um mass median aerodynamic diameter was delivered into the device of Figure 1 and decrease of aerosol concentration was monitored continuously by a light scattering aerosol photometer while a subject rebreathed the aerosol at a rate of 30 breaths/minute. The aerosol was generated by a Sinclair-LaMer type aerosol generator using di-2 (ethyl hexyl) sebacate oil. Size distribution of the aerosol was measured by a Rayco 220 optical counter with a multichannel analyzer.

Drug administration protocol involved a study conducted on a modified randomized single-blind cross¬ over basis. The patient did not know whether 5-[l- hydroxy-2-[ (1-methylethyl)amino]ethyl]-benzene diol or 4-hydroxy-3-hydroxymethyl-alpha-[ (tert-butylamino)meth¬ yl]benzyl from metered dose inhaler was being adminis¬ tered and the technician performing the pulmona

function tests which method or drug was being tested. The effect of one puff of 5-[l-hydroxy-2-[ (1-methyl¬ ethyl) amino]ethyl]-benzene diol (650 ug) via the inven¬ tion was compared with one puff of 5-[l-hydroxy-2-[ (1- methylethyl)amino]ethyl]-benzene diol and' one puff of 4-hydroxy-3-hydroxymethyl-alpha-[ (tert-butylamino)meth¬ yl]benzyl (100 ug) delivered by a conventional metered dose inhaler. All patients had used a metered dose inhaler regularly and had been instructed in their administration at least several months previously. Shortly before the study, all received further training from one of the investigators and were given instruc¬ tions developed by Newman et al ["Simple Instructions for Using Pressurized Aerosol Bronchodilators", J. Royal Soc. Med. , Vol. 73, pp 776-779 (1980)]: to shake the canister, place the mouthpiece of the metered dose inhaler between the lips while exhaling to FRC, to release the metered dose inhaler while performing a slow, deep inspiration to total lung capacity and to breathhold at this lung volume while counting to ten.

Respiratory Inductive Plethysmography was deter¬ mined in the following manner. A detailed description of the DC-coupled respiratory inductive plethysmograph and its calibration (Respitrace®, Non-Invasive Monitoring Systems, Inc., Ardsley, NY) is being pub¬ lished by Chahda et al, ["Validation of Respiratory Inductive Plethysmography Utilizing Different Calibration Procedures", Amer. Rev. Respir. Dis. (in press) ] . It consists of two coils of Teflon insulated wire sewn into elastic bands encircling the rib cage and the abdomen which are connected to an oscillator module. Changes in cross-sectional areas of the rib cage and abdomen compartments alter the self inductance of the coils and. the frequency of their oscillations, which after appropriate calibration, reflect tidal volume measured by spirometry. Assuming that the respiratory systems moves with two degrees of freedom, the device is

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calibrated using rib cage, abdomen, and spirometer volumes and the equation rib cage/spirometer + abdo¬ men/spirometer ^** - ^* 1. The subject breathes into a spiro¬ meter in two body postures to produce differences in rib cage and abdominal contributions to tidal volume and the equation is solved, graphically. Validation of the calibration of respiratory inductive plethysmography is performed against simultaneous spirometry in the upright and supine positions and the mean (± SD) percentage deviation from spirometry in the patients was 4.1 ± 2.4% and 4.6 ± 2.8%, respectively.

The signals from the respiratory inductive plethys- mograph were recorded on a Z-80A based microprocessor system (Respiσomp®, Respitrace Corp. , Ardsley, NY) which sampled the signals at 20 points/sec. At the moment of actuation of the metered dose inhaler, an observer signalled the computer with an analog step voltage. Later, the recording was analyzed by a cursor program and the computer calculated the following parameters:

(1) change in lung volume from FRC to actuation of metered dose inhaler,

(2) change in lung volume from actuation of metered dose inhaler to peak inhalation,

(3) durations of (1) and (2) and the breathholding time until subsequent exhalation,

(4) mean inspiratory flow rates from FRC to actuation and from actuation to peak inhalation.

Statistical differences among the three treatments for improvement in lung function were analyzed by a nested factorial design of Hicks et al, ["Nested and Nested Factorial Experiments", Fundamental Concepts in the Design of Experiments 2 Edition, (1973) Holt, Rinehart and Winston Inc., New York, pp. 188-203 ] . This took into account variation in baseline measure¬ ments between the study days. If significance was found, the data were further analyzed by Q statistics to define which of the treatments produced the greatest

response. Paired t-tests were also performed to compare the effects of the three treatments at each time inter¬ val after bronchodilator. The bronchodilator results in patients with a good metered dose inhaler technique were compared to those with a poor technique using an un¬ paired t-test. The results were expressed as means ± standard error (X ± S.E.)

The size distributions measured by the 6-stage cascade i pactor were approximately log-normal, with 5-[l-hydroxy-2-[ (1-methylethyl)amino]ethyl]-benzene diol having a mass median aerodynamic diameter of 4.9 (SD ± 0.8) um with geometric standard deviation of 2.1 and 4-hydroxy-3-hydroxymethyl-alpha-[ (tert-butylamino)meth¬ yl]benzyl having a mass median aerodynamic diameter of 2.4 (SD ± 0.28) um with geometric standard deviation of 1.7.

The impaction loss- from the metered dose inhaler on the surface of the oropharyngeal model was 43% for 5-[l-hydroxy-2-[ (1-methylethyl)amino]ethyl]-benzene diol and 31% for 4-hydroxy-3-hydroxymethyl-alpha-[ (tert- butylamino)methyl]benzyl. When the 5-[l-hydroxy-2- [ (1-methylethyl)amino]ethyl]-benzene diol was delivered into the air bag of the aerosol delivery system of Figure 1, 50% of the aerosol was recovered by flushing the bag five times with clean air, indicating the 41% of the aerosol was lost in the device of Figure 1. When attached to the glass model, 6% of the 5-[l-hydroxy-2- [ (1-methylethyl)amino]ethyl]-benzene diol aerosol from device of Figure 1 was deposited on the model. There¬ fore, for 5-[l-hydroxy-2-[ (1-methylethyl)amino]ethyl]- benzene diol, 47% of the aerosol was lost combined with the glass model leaving potentially 53% to enter the airways.

Determination of the number of breaths for airway deposition of aerosol was obtained in four normal sub¬ jects and four patients with chronic bronchitis. In the normal subjects, the number of breaths at which 90% of

the initial aerosol in the device of Figure 1 was re¬ tained in the lung was 4.8 (SD ± 0.8), while in the patients with chronic bronchitis, it was 1.8 (SD ± 0.8). Thus, in the patients it was felt that one .breath from the device of Figure 1 followed by a second breath of rebreathing from the bag together with breathholding between breaths would provide optimal deposition of aerosol without significantly increasing alveolar carbon dioxide.

The response to bronchodilators was analyzed with mean changes of pulmonary functions indices with three treatments. SG increased greater than 70% with all three treatments but the response to 5-[l-hydroxy-2-[ (1- methylethyl)amino]ethyl]-benzene diol via the device of Figure 1 was at all times significantly greater than with 5-[l-hydroxy-2-[ (1-methylethyl)amino]ethyl]-benzene diol or 4-hydroxy-3-hydroxymethyl-alpha-[ (tert-butyl¬ amino)methyl]benzyl administered by metered dose inhaler (p less than .003). There was no significant difference between 4-hydroxy-3-hydroxymethyl-alpha-[ (tert-butyl¬ amino)methyl]benzyl and 5-[l-hydroxy-2-[ (1-methyl¬ ethyl)amino]ethyl]-benzene diol delivered by metered dose inhaler with maximal increases in SGaw of 86 ±

26% and 101 ± 24%, respectively, compared to the maximal increase of 195 ± 52% with 5-[l-hydroxy-2-[ (1-methyl¬ ethyl)amino]ethyl]-benzene diol delievered via the invention. Two hours after administration of broncho¬ dilator, a fall from the maximal value of SGaw was observed with 4-hydroxy-3-hydroxymethy1-alpha-[(tert- butylamino)methyl]benzyl and 5-[l-hydroxy-2-[ (1-methyl¬ ethyl)amino]ethyl]-benzene diol whereas the response to 5-[l-hydroxy-2-[ (1-methylethyl)amino]ethyl]-benzene diol via the device of Figure 1 was still well maintained.

A greater increase in FEV. was more frequently observed with 5-[l-hydroxy-2-[ (1-methylethyl)amino]eth¬ yl]-benzene diol via the device of Figure 1 compared to 4-hydroxy-3-hydroxymethyl-alpha-

[ (tert-butylamino)methyl]benzyl or

5-[l-hydroxy-2-[ (1-methylethyl)amino]ethyl]-benzene diol and mean maximal increases were 47 ± 13%, 24 ± 8% and 22 ± 8%, respectively, but these differences did not reach group statistical significance. Similarly, a greater increase in FVC was observed more frequently with 5-[l-hydroxy-2-[ (1-methylethyl) amino]ethyl]-benzene diol via the device of Figure 1 than with 4-hydroxy-3-hydrσxymethyl-alpha-[(tert-butylamino)methy- l]benzyl or 5-[l-hydroxy-2-[ (1-methylethyl)a- mino]ethyl]-benzene diol and the maximum increases were 36 ± 11%, 13 ± 4% and 9 ± 4% ^' , respectively. A signifi¬ cant difference was observed 30 minutes after 5—[1- hydroxy-2-[ (1-methylethyl)amino]ethyl]-benzene diol via the invention compared to conventional metered dose inhaler, 36 ± 11% and 13 ± 4%, respectively, (p less than .05) . A reduction in FRC was observed with all treatments and was marginally greater with 5-[1-hydroxy- 2-[ (1-methylethyl)amino]ethyl]-benzene diol via the invention compared to the other treatments (p = 0.054).

Metered dose inhaler technique was studied in the following manner: Although all patients were regular users of metered dose inhaler (12.6 years average duration of use) , and had received retraining a few days before the study, few succeeded in operating the conven¬ tional metered dose inhaler in accordance with the instructions they had received. Four patients were unable to coordinate metered dose inhaler actuation with the period of inhalation. One patient inhaled approxi¬ mately 1 liter and breathheld for 6 seconds before actuating the metered dose inhaler and then immediately exhaled. A second patient actuated the inhaler during the expiratory phase after a deep inspiration, and a third patient actuated it at peak inspiration of a tidal breath, exhaled and the took a prolonged deep inhala¬ tion. The fourth patient actuated the inhaler while expiring and then proceeded to take a deep inspiration.

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All of these patients were able to use the device of Figure 1 without difficulty.

Among the six patients who succeeded in actuating the inhaler during inspiration, most actuated it after they had inhaled approximately .5 liter of air. Follow¬ ing actuation, the average inhalation volume was 2 liters with a breathhold pause of 14 seconds. There was considerable variation in inspiratory flow rates and in the six patients with good metered dose inhaler techni¬ que, the mean flow rates were 1.02 ± .29 L/sec and .54 ± .16 L/sec during inhalation of 4-hydroxy-3-hydroxy- methyl-alpha-[ (tert-butylamino)methyl]benzyl and 5-[l- hydroxy-2-[ (1-methylethyl)amino]ethyl]-benzene diol, respectively, compared to .19 ± .02 L/sec and .24 ± .03 L/sec during the first and second inhalations, respec¬ tively in all ten patients while using the device of Figure -1. The highest inspiratory flow rate with the device of Figure 1 was .50 L/sec compared to 1.90 L/sec with conventional metered dose inhaler.

A distinct difference was noted in the broncho¬ dilator response to conventional metered dose inhaler administration between the patients with good technique defined .as actuation of metered dose inhaler during inspiration irrespective of flow rate in contrast to poor technique defined as actuation of metered dose inhaler during breathholding or exhalation. The maximal increase in after 5-[l-hydroxy-2-[ (1-methyl- ethyl)amino]ethyl]-benzene diol via metered dose inhaler was 150 ± 23% in the six patients with a good technique compared to 27 ± 9.3% in the four with a poor technique

(p less than .005) . When the latter used the invention, three showed a maximal averag ³ e incresae in SGaw of 163

± 90% and one response comparable to that with con¬ ventional metered dose inhaler. Among the six patients with good metered dose inhaler technique the maximal response of SGaw to the device of Figure 1 of 236 ±

78% was considerably higher than the maximal response of

150 ± 23% with metered dose inhaler delivering 5-[l- hydroxy-2-[ (1-methylethyl)amino]ethyl]-benzene diol.

Figure 2 illustrates a further embodiment of the invention. This embodiment has structure that enables it to be "used for inhalation through the nose, allowing the nasal passages to be coated with the desired drug. The embodiment of Figure 2 employs the basic nebulizer assembly 56 as shown in Fig. 1 with piece 19 and pres¬ surized inhaler bottle 21. Mask 45 is provided for the patient with soft gasket 46 to improve sealing of the mask from outside air. Although mask 45, as shown, is applied by the patient over his nose and mouth, it is also contemplated that a mask could be used which is applied only over the nose of the patient. Mask 45 has aperture 48 located on the bottom portion thereof for the communication of the drug into the mask. Tube 47 connects aperture 48 of mask 45 to piece 19 of nebulizer assembly 56. Tube 47 may be made of a pliable plastic or other suitable material for securing around piece 19. Any other type of connection between tube 47 and mouth¬ piece 19 as would be known of by one ordinary skill in the art is also contemplated by this description. Nebulizer assembly 56 attaches to mounting portion 57 of airbag assembly 50. Airbag assembly 50 is comprised of apertured end cap 51 and end cap 52 connected together by sidewalls 53. Apertured end cap 51, end cap 52 and sidewalls 53 form cavity 54. Apertured end cap 51 and end cap 52 may be made of commercially available plastic material. It is contemplated that walls 53 are made of 2% mil polyethylene, although they may be composed of any suitably flexible and light material. Side walls 53 would be connected to apertured end cap 51 and end cap 52 by heat sealing around the peripheries 58 thereof. The design of air.bag assembly 54 can be of any suitable materials such that it provides a gas impermeable closed bag that may be attached to nebulizer assembly 56. It is particularly contemplated that the apertured end cap

and the end cap may be manufactured in such a manner that it is easily portable and may fit in the pocket of any user. When apertured end cap 51 is detached from nebulizer assembly 56 with a twisting motion, apertured end cap 51 may be rotated in relation to end cap 52 to form a flat assembly with the side walls 53 automati¬ cally folded up therebetween. In addition, nebulizer 56 may be detached from mask 45 and tube 47 and these pieces may also be fit into the patient's pocket. These pieces, working in concert, provide for an easily as¬ sembled and easily used, highly effective apparatus.

The drug delivery device of the invention offers distinct advantages over the prior art drug delivery systems where the drug is "puffed" from a conventional inhaler, such as the pressured dosage inhalers that are used for 5-[l-hydroxy-2-[ (1-methylethyl)amino]ethyl]- benzene diol and 4-hydroxy-3-hydroxymethyl-alpha-[ (tert- butylamino)methyl]benzyl alcohol of the prior art of Boehringer Ingelheim and Shering (or Glaxo) , respec¬ tively. When compared with the spacer systems that have been proposed, the airbag system embodied in the inven¬ tion has distinct advantages. The airbag system com¬ pares favorably in terms of a minimal .patient coordina¬ tion being needed during the administration of the drug. The signal means of the invention provides for patient awareness of the flow rate and volume of air during administration of the drug, a further advantage over the spacer system that has been proposed. Repro¬ ducible dosing of. the drug through a metered puff of the drug into the airbag is also an advantage of the inven¬ tion particularly over the conventional inhalers that have been proposed for 5-[l-hydroxy-2-[ (1-methylethyl)a- ino]ethyl]-benzene diol and 4-hydroxy-3-hydroxymethyl- alpha-[ (tert-butylamino)methyl]benzyl alcohol in the prior art. A further advantage over both the inhalers for 5-[l-hydroxy-2-[ (1-methylethyl)amino]ethyl]-benzene diol and 4-hydroxy-3-hydroxymethyl-alpha-[ (tert-

butylamino)methyl]benzyl alcohol as well as the spacers that have been proposed is the more even distribution of the drug throughout the inhalation maneuver by the patient. Conservation of medication through the more efficient distribution of the drug is a further advan¬ tage of the airbag system of the invention.

In particular, the ease of use by the patient is particularly important, minimal demands being placed on the patient for routine use of the airbag system of the invention, a point which is underscored by the studies mentioned in discussion of the background of the inven¬ tion which show that many patients for even conventional 5-[l-hydroxy-2-[(1-methylethyl)amino]ethyl]-benzene diol and 4-hydroxy-3-hydroxymethy1-alpha-[ (tert-butylami¬ no)methyl]benzyl alcohol inhalers fail to properly use the systems. The signal means, preferably the reed whistle embodied in a preferred aspect of the invention, "trains" the patient on proper breathing techniques for the administration of the drug, and of course provides a built-in aid to signal the patient when he has exceeded the desirable maximum amount of air flow rate; in this manner, the patient learns how to perform the slow inspiratory flow maneuver and the magnitude of the "deep, breath" that is advantageously taken for the administra¬ tion of pulmonary medications. Minimization of the deposition of aerosol in the oropharynx is another consequence of the use of the invention with the con¬ trolled delivery of the drug from the airflow from the airbag, vis a vis the "puff" of drug with an inhaler for 5-[l-hydroxy-2-[ (1-methylethyl)amino] thyl]-benzene diol or 4-hydroxy-3-hydroxymethyl-alpha-[ (tert-butylamino)- methyl]benzyl alcohol that provides too much of the drug at one time. Reproducible dosing to the tracheobron¬ chial tree is similarly maximized. To provide an even distribution in the tracheobronchial tree it is advan¬ tageous that there should be even distribution of the medication throughout the inhalation maneuver. Quite

apart from the simplicity of construction and porta¬ bility of the device of the invention and the other advantages noted above, it is to be particularly recog¬ nized that with the drug delivery device of the inven¬ tion, a more effective drug administration ^' is promoted than with 5-[l-hydroxy-2-[ (1-methylethyl)amino]ethyl]- benzene diol or 4-hydroxy-3-hydroxymethyl-alpha-[ (tert- butylamino)methyl]benzyl alcohol inhalers now on the market, with a minimization of drug being introduced into the system of the patient other than through the desired tracheobronchial tree.

The volume of the airbag for delivery of drug to the tracheobronchial tree via the mouth is typically 700 cc when the airbag is in its fully expanded state, although variations of from about 500 cc to about 1500 cc may be used in preferred aspects of the invention. A relatively smaller volume should be used for delivery to the nasal mucous passages, with 100 cc being a suitable maximum expanded volume for an airbag adapted for this use. The smaller volume provides a sufficient quantity of air to force the drug through the entire mucous membrane area of the nose, substantially more air provi¬ ding for the propulsion of the contents of the airbag further into the patient, which in one embodiment of the invention (where delivery only to the nasal passages is desired) should be avoided. It is to be understood that if the drug is to be delivered beyond the nasal passages that a larger maximum air capacity for the airbag may be used, although in such applications it is to be under¬ stood that the drug will generally be delivered through the mouth.

With respect to rate of air that is used to trigger the signal means, those skilled in the art will under¬ stand that the rate at which the signal is triggered may be varied dependent upon the desired rate. In the invention for delivery of 5-[l-hydroxy-2-[ (1-methyl¬ ethyl)amino]ethyl]-benzene diol, it is desired to have

MPI

the signal triggered with an inspiratory flow rate which exceeds 20L/min, as one embodiment of this invention. A reed whistle is typically placed in the bidirectional channel so that as air is inhaled at a rate greater than 20L/min, an audible whistling sound is emitted, thereby signalling the patient to slow down his rate of air intake, thereby avoiding too great a rate of intake and the attendant previously mentioned disadvantages.

In experiments conducted with a drug delivery device in accordance with the invention it was observed that virtually all of the loss of aerosol by impaction occurs in the airbag with none in the glass oropharyn- geal model, demonstrating the superiority of the inven¬ tion in terms of avoidance of medication entering the patient's system other than through the tracheobronchial tree. The extent of aerosol loss in the bag is similar to loss in the model when metered aerosol is directed into the model. Studies on aerosol retention in normal and bronchitic subjects who rebreathed 2.5 um mass median aerodynamic diameter aerosol of di-2-ethylhexyl sebacate from a 0.5 L reservoir bag at 10 breaths per minute. A discussion of measurements of this type for the invention is made in Brown et al, "Measurement of Aerosol Retention Using a Rebreathing Technique in Normal and Chronic Brochitics", in publication for Am. Rev. Resp. Pis, (in press). In normal subjects, 90% retention occurred at 4.6, SD 0.7 breaths and in brochi¬ tics 3.2, SD 0.7 breaths (p less than 0.01). Preli¬ minary data in bronchitics indicate that 90% retention of aerosols of mass median aerodynamic .diameter 4 um (size of metered aerosol particles) ought to occur within 2 breaths. Apart from drug loss in the airbag, the drug delivery device of the invention provides su¬ perior delivery of oronasally delivered drugs in com¬ parison with known devices of the prior art such as the conventional inhalers for 5-[l-hydroxy-2-[ (1- methylethyl)amino]ethyl]-benzene diol and 4-hydroxy-3-

hydroxymethyl-alpha-[ (tert-butylamino) ethyl]benzyl alcohol, and share in common with such inhalers a sim¬ plicity of construction and economy of manufacture to make their routine use simple for patients who are able to carry the collapsed airbag in a small' pocket pouch and instantly assemble the airbag and piece for use when required even outside the home.

In accordance with a further aspect of the present invention the compound 6alpha-flouro- llbeta,Iδalpha,17,21-tetrahydroxypregna-l,4-diene-3,20- dione cyclic 16,17-acetal may be used as an agent for the ^" treatment of bronchial asthma when administered via the tracheobronchial tree via a mouthpiece such as shown in Figure 1. The drug is administered to the patient in the same manner as in Figure 1, and provides relief from bronchial asthma. The drug 6alpha-flouro- llbeta,16alpha,17,21-tetrahydroxypregna-l,4-diene-3,20- dione cyclic 16,17-acetal is presently known for a different application via nasal administration under the trademark Nasalide (Syntex Laboratories, Inc., Palo Alto, California) . When 6alpha-flouro- llbeta,16alpha,17,21-tetrahydroxypregna-l,4-diene-3,20- dione cyclic 16,17-acetal is administered via the mouth to the tracheobronchial tree for relief from bronchial asthma in accordance with the present invention, a spray of Nasalide may be used for introduction into the airbag in accordance with Figure 1. One puff (30 meg) of Nasalide is contemplated as a dosage to be administered two times per day as one embodiment of the present invention as a treatment for bronchial asthma.

In accordance with a still further aspect of the present invention, it is contemplated that the compound 6alpha-flouro-llbeta,lδalpha,17,21-tetrahydroxypregna- 1,4-diene-3,20-dione cyclic 16,17-acetal may be used for allergic rhinitis when administered nasally in accor¬ dance with the embodiment of Figure 2. The use of 6alpha-flouro-llbeta,Iδalpha,17,21-tetrahydroxyρregna-

iREA

l,4-diene-3,20-dione cyclic 16,17-acetal for the treat¬ ment of allergic rhinitis is known from the commercial use of Nasalide which is nasally administered. Just as nasal administration set forth for the embodiment of Figure 2 provides for a more even distribution of the drug to the nasal mucous passages while minimizing the entry of the drug into the system of the patient through other means, so too is this advantage to be obtained in for the administration of 6alpha-flouro- llbeta,16alpha,17,21-tetrahydroxypregna-l,4-diene-3,20- dione cyclic 16,17-acetal. It is contemplated that with a spray of Nasalide one puff (30 meg) delivered twice a day should be administered in accordance as one embodi¬ ment of this aspect of the present invention.

It should be noted that the airbag of the present invention is described as being "impervious" to the passage of drug. It is to be understood that materials such as polyethylene which are contemplated as a material for the airbag of the present invention permit the passage of drug molecules at a relatively slow rate used, for example, as solubility membranes for trans- dermal drug delivery systems. It is therefore to be understood that by "impervious" is contemplated materi¬ als which are substantially impervious to the passage of drug molecules for use in the invention where the drug only briefly contacts the airbag, polyethylene and other such materials being within the scope of the invention as materials suitable for the construction of the air¬ bag. It is also to be appreciated that in an embodiment of the invention it is contemplated that an airbag material that would be substantially impervious to the passage of drug but which could permit passage of air therethrough could advantageously be used in the present invention, although currently there is no practical material that would satisfy this particular aspect of the present invention.

It is also to be noted that for some patients a signal means such as the reed whistle may .not prove satisfactory, which is particularly the case with pedi- atriσ and geriatric patients. ^* Children are less likely to obey the "command" of the whistle, either through lack of understanding or a general lack of discipline in following a doctor's instructions that would be expected in an adult. Geriatric patients often encounter a hearing problem. Accordingly, the airbag of Figure 1 may be modified to include within the said bidirectional channel an air resistor means whereby even with great efforts on the part of the patient it is not readily possible to exceed a certain maximum airflow passage through the said bidirectional channel, i.e., a certain maximum airflow that would otherwise be controlled by the signal means could be the built-in maximum airflow for said bidirectional channel by virtue of inclusion in that bidirectional channel of a resistor means. As a resistor means illustrated in Figure 3 (which shows only a portion of the mouthpiece of the embodiment of Figure 1) there is included a washer-shaped disc 65, the amount of air which may pass through said bidirectional channel being restricted by the the washer-shaped disc 65 having orifice 67. The washer-shaped disc 65 is also shown in Figure 4. In addition to the washer-shaped disc 65 other resistor means include a screen member 66 having frame 68 with screen 69 stretched across frame 68 shown in Figure 5 which is substituted for the washer-shaped disc 65 in the configuration otherwise in accordance with Figure 4. As an alternative to the resistor means which are found in Figures 4 and 5, and other obstruc¬ tion within the bidirectional channel which will de¬ crease the amount of air which may pass through said bidirectional channel per unit time may be substituted therefor, or a portion or all of the bidirectional channel between the point at which the drug enters the airbag to the point of communication with the mouth may

^■• ξυfcE

OMPI

-30-

have a narrower cross-sectional area than the area of the bidirectional channel between the point of entry of the aersolized drug and the airbag.

In a further embodiment of the invention where it is desired to have very minute particles administered to the tracheobronchial tree, a screen may be used such as shown in Figure 5 which only admits very small par¬ ticles. For example, in the case of gram negative pneumonia, it is desirable to treat the deepest reaches of the lung with the active agent, for example, gentimi- cin sulfate. If the spray of the drug has large parti¬ cles, the larger particles will "hit" the tracheo¬ bronchial tree at points before reaching the deep areas of the lung. By providing a screen that permits passage of only small particles, e.g., having a diameter less than about 0.1 micron, the patient will receive a drug spray where a significant portion of the drug will reach the desired deepest reaches of the lung. In one embodi¬ ment of this aspect of the invention where gentimycin sulfate is the drug used for treatment of gram negative pneumonia, a typical dosage would be 60 mg of the drug in an aerosolized puff through the device of Figure 1, modified with a screen permitting passage only of par¬ ticles having a diameter of less than 0.1 microns as modified in accordance with Figure 5.