METERED DOSE INHALER WITH AN INTEGRATED COUNTER

INTRODUCTION

Aspects of the present invention relate to metered dose inhalers and a method of using metered dose inhalers for pulmonary administration of drugs. An aspect of the invention relates to metered dose inhalers having a multipart actuator with an integrated mechanical counter with a color indicator that indicates the approximate number of doses remaining to be dispensed.

Drugs for treating respiratory and nasal disorders are frequently administered in aerosol formulations through the mouth or nose. One widely used method for dispensing such aerosol drug formulations involves making a suspension formulation of the drug as a finely divided powder in a liquefied gas known as a propellant. The suspension is stored in a sealed container capable of withstanding the pressure required to maintain the propellant at least partially as a liquid. The suspension is dispersed by activation of a dose metering valve affixed to the container.

A metered dose inhaler (MDI) is a pharmaceutical delivery system that is commonly used to administer inhaled prescription drugs to treat a variety of conditions, including bronchospastic conditions such as asthma. MDI products contain aerosols which are generally solutions, primary emulsions, or suspensions of the active constituent along with propellant contained in a pressurized canister.

A conventional MDI consists of: 1) a canister, usually made of metal, frequently approximately 5 cm high and 2.5 cm in diameter, 2) a metered dose valve and dispensing nozzle that are affixed to the top of the canister and are used to deliver a fixed quantity of the dose when the nozzle is depressed, 3) a plastic cap ("mouthpiece") that is used to actuate the dispensing nozzle and to direct the dose into the patients lungs through the mouth; and 4) the contents of the canister, which usually consists of a mixture of an aerosol propellant and drug that is mixed or suspended in the propellant. The aerosol propellant acts as a carrier medium to deliver the drug. A propellant may be a single aerosol or a mixture of aerosols.

A metering valve may be designed such that upon activation, it consistently releases a fixed, predetermined volume of the drug formulation. As the formulation is forced from the container through the dose metering valve by the high vapour pressure of the propellant, the propellant rapidly vaporizes, leaving a fast moving cloud of very fine particles of the drug formulation. This cloud of particles is directed into the nose or mouth of the patient by a channeling device such as an open-ended cylinder or cone. Concurrently, with the activation of the aerosol dose metering valve, the patient inhales the drug particles into the lungs or nasal cavity. Systems for dispensing drugs in this way are known as "metered dose inhalers" (MDIs). MDIs are commonly used to treat asthma, chronic obstructive pulmonary disease and other respiratory problems.

MDI products currently offer the benefits of bronchodilators, steroids, and other drugs with less systemic effects than would normally be observed following intravenous therapy or oral dosage forms such as tablets. The MDI products also may be applied to the delivery of drugs such as leukotriene antagonists as well as proteins and peptides.

The effective dose of drug delivered from an MDI product should be adequate and reproducible from actuation to actuation when treating a patient with asthma. For example, inappropriate and variable doses of bronchodilators during an acute asthmatic attack can have life-threatening consequences. Moreover, corticosteroids are often administered chronically to patients with asthma as a prophylactic measure and a high degree of dose-to-dose uniformity offers the greatest amount of protection. Two major determinants of the effective dose which a patient receives from a metered dose inhaler product are the dose delivered from the MDI, as well as the size of the particles inhaled into the pulmonary system.

Another consideration is that MDI pharmaceutical manufacturers typically label the packaging and/or the MDI with a "labeled dose", which is the maximum number of doses to be used. MDI products typically contain overfill to ensure good dose to dose reproducibility for the number of "labeled doses" of the product, and to allow for priming the metering chamber of the canister valve. For these reasons, it is essential that the device delivers an accurate and consistent dose from actuation to actuation from the first dose until the "labeled dose" is reached. It is also important that the particle size is maintained at a level acceptable to penetrate deeply into the pulmonary tree for maximum efficacy. The current manufacturing practice of overfilling MDI products permits actuation of the MDI well beyond the "labeled dose".

When the "labeled doses" are exceeded, the dose strength could result in suboptimal therapy.

Patients often rely on medication delivered by MDIs for rapid treatment of respiratory disorders which are debilitating and in some cases, even life threatening. Therefore, it is essential that the prescribed dose of aerosol medication delivered to the patient consistently meets the specifications claimed by the manufacturer and complies with the requirements of the FDA and other regulatory authorities, that is, every dose in the can must be the same within close tolerances.

One approach to identifying each actuation of an MDI and to determining the number of actuations for a given canister is seen in U.S. Patent No. 5,020,527. However, the actuation of the MDI is identified by the mechanical operation of a lever each time the canister is depressed for delivery of a dose, and the number of actuations of the lever is counted. This approach is deficient because the requirement for a mechanical actuation of a switch presents the greater possibility of false actuations or failed actuations, thereby providing erroneous readings.

Another approach to identify each actuation of an MDI is seen in U.S. Patent No. 5,676,129, where a pressure sensor is used to measure the pressure changes in the transfer channel of the mouthpiece of an MDI delivery system. Pressure changes may result from one or both of the dispensing of a dose and the inhalation process of a patient, or may also result from the effect of other events.

Yet another approach to identify each actuation of an MDI is seen in U.S. Patent Application Publication No. 2006/0254581, using electronic monitoring and counting of medication doses and, in particular, a metered dose inhaler that includes an electronic counter module.

Currently available MDIs offer no practical way for a user to monitor the remaining number of doses or amount of medication. A complicating, but necessary design feature in the formulation of an MDI is that they contain more doses than the label claim. Additional amounts of formulation are filled to ensure dosing consistency of each spray through the labeled number of doses. However, the amount of drug per spray after the label claim doses have been administered is inconsistent and might not provide the required therapeutic effect.

Currently, patients are facing the problem of identifying the number of doses remaining in the MDI. Due to this, they sometimes discard a canister that may still contain acceptable metered doses or use the product until the last puff, with the risk of not receiving the correct medicament in the later doses.

Apart from the above critical disadvantages, a spray can be actuated even when the dust cap is closed, thus contaminating the nozzle hole and providing a waste of doses. Also, dust caps can be misplaced, exposing the nozzle.

There are no easy, reliable means currently available to the patient to determine when a canister's "labeled" contents have been consumed and that the patient has reached the "labeled dose" limit. Typically, patients will use metered dose inhaler products until the entire canister is exhausted. This could represent 25% or more actuations beyond those labeled for a pharmaceutical product. Thus, a mechanism which would aid the patient in tracking the number of actuations which have been used for a given canister would aid the patient in determining when an MDI canister should be discarded and a new MDI canister used. The development of such a device would enhance the ability of a patient to comply or adhere to a prescribed dosing regimen.

Any improvement in the treatment of asthma could result in reduced hospital stays and reductions in related health care costs. From an economic standpoint, this would be highly desirable.

SUMMARY

In aspects, the present invention of metered dose inhalers integrated with a dose counting device, either through a direct numeric count or color coding, helps to show when an MDI is approaching the end of its recommended number of doses, and thus, enables tracking the remaining number of doses or amount of medication.

Aspects of the present invention include low cost MDI models that may be dispensed with each canister prescription.

According to embodiments of the present invention, a metered dose inhaler comprises:
a housing or main body with a display window;
a dose counter assembly or integrated mechanical counter; and
a mouth piece provided with rotary moving shutter.

Embodiments of the present invention relate to metered dose inhalers with decrementing dose counter assemblies that indicate the approximate number of doses remaining. An embodiments of a dose counter assembly includes a dose counter slider having a color indicator that indicates the approximate number of doses remaining.

In specific embodiments, the present invention relates to metered dose inhalers comprising a dose counter assembly having:

a rotatable dose counter rotor fixed in a dose counter casing through fixed slots;

a dose counter actuator inserted over the dose counter rotor in bracket slots provided in the dose counter casing; and

a dose counter slider with a color indicator inserted from the lower side into vertical guide slots of the dose counter casing.

The dose counter slider has a color indicator that can be seen through a display window in the housing. Thus, the present invention relates to a method of counting the number of doses delivered from, or remaining in, an MDI using a dose counter assembly having a color indicator.

The present invention includes metered dose inhalers wherein the entire housing assembly is placed in line with the nozzle, without interfering with the emitted spray. An MDI of the present invention also includes a housing having an integrated dust cap, to cover the mouthpiece and which functions as a spacer.

The main housing of the metered dose inhaler includes a display window through which the color indicator indicates the number of doses remaining to be dispensed.

The metered dose inhaler also prevents actuation when a shutter is closed, thereby preventing loss of the medicament.

In embodiments, the metered dose inhaler is used for pulmonary administration of drugs.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a side perspective view of a assembled metered dose inhaler with the counter according to the present invention.

Fig. 2 is a front perspective view of an assembled metered dose inhaler of Fig. 1.

Fig. 3 is a rear elevational view of an assembled metered dose inhaler of Fig. 1.

Fig. 4 is a top plan view of an assembled metered dose inhaler of Fig. 1.

Fig. 5 is an enlarged cross-sectional view of an assembled metered dose inhaler of Fig. 4, taken along line 5-5 thereof.

Fig. 6 is an exploded, perspective view of an assembled metered dose inhaler of Fig. 1.

Fig. 7 is a perspective view of a main housing.

Fig. 8 is a side elevational view of a main housing.

Fig. 9 is a top plan view of a main housing.

Fig. 10 is an enlarged side elevational view of a bottom portion of a main housing.

Fig. 11 is an enlarged cross-sectional view of the circled portion of the main housing of Fig. 12, showing the seat for the canister.

Fig. 12 is a cross-sectional view of a main housing of Fig. 9, taken along line 12-12 thereof.

Fig. 13 is a cross-sectional view of a main housing of Fig. 9, taken along line 13-13 thereof.

Fig. 14 is a perspective view of a mouthpiece.

Fig. 15 is a front elevational view of a mouthpiece.

Fig. 16 is a top plan view of a mouthpiece.

Fig. 17 is a side elevational view of a mouthpiece.

Fig. 18 is a cross-sectional view of the .mouthpiece of Fig. 15, taken along line 18-18 thereof.

Fig. 19 is a perspective view of a shutter.

Fig. 20 is a top plan view of a shutter.

Fig. 21 is a cross-sectional view of the shutter of Fig. 20, taken along line 21-
21 thereof.

Fig. 22 is a cross-sectional view of the shutter of Fig. 20, taken along line 22-
22 thereof.

Fig. 23 is a top perspective view of a dose counter casing. Fig. 24 is a bottom perspective view of a dose counter casing. Fig. 25 is a top plan view of a dose counter casing.

Fig. 26 is a side elevational view of a dose counter casing.

Fig. 27 is a front elevational view of a dose counter casing, partially in phantom.

Fig. 28 is a top perspective view of a dose counter rotor.

Fig. 29 is a bottom perspective view of a dose counter rotor.

Fig. 30 is a top plan view of a dose counter rotor.

Fig. 31 is a cross-sectional view of the dose counter rotor of Fig. 30, taken along line 31-31 thereof.

Fig. 32 is a cross-sectional view of the dose counter rotor of Fig. 30, taken along line 32-32 thereof.

Fig. 33 is a bottom perspective view of a dose counter actuator.

Fig. 34 is a side elevational view of a dose counter actuator.

Fig. 35 is a top plan view of a dose counter actuator.

Fig. 36 is a cross-sectional view of the dose counter rotor of Fig. 30, taken along line 36-36 thereof.

Fig. 37 is a perspective view of a dose counter slider.

Fig. 38 is a front elevational view of a dose counter slider.

Fig. 39 is a bottom plan view of a dose counter slider.

Fig. 40 is a cross-sectional view of the dose counter slider of Fig. 38, taken along line 40-40 thereof.

Fig. 41 is a top perspective view of a top cover.

Fig. 42 is a top plan view of a top cover.

Fig. 43 is a cross-sectional view of the top cover of Fig. 42, taken along line 43-43 thereof.

Fig. 44 is a cross-sectional view of the top cover of Fig. 42, taken along line 44-44 thereof.

Fig. 45 is an enlarged cross-sectional view of a portion of the top cover of Fig. 44.

DETAILED DESCRIPTION

Aspects of the present invention are directed to metered dose inhalers (MDIs), primarily used for pulmonary administration of drugs. In embodiments, a metered dose inhaler according to the present invention includes a multipart actuator with an integrated mechanical counter or dose counter assembly having indicia to indicate the approximate number of doses remaining therein.

Inadvertent actuation of currently available metered dose inhalers can occur due to accidental actuation or accidental impact of the device, or be due to unanticipated events, for example, when the device is carried in a pocket, misuse by children, etc.

In further embodiments, a metered dose inhaler according to the present invention has an integrated dust cap to prevent unintended actuation, and also prevents the possibility of losing the dust cap.

In embodiments, special features of an MDI according to the present invention include:

a safety feature that prevents actuation when the cap is closed, and

a sleek design to meet ergonomic requirements of the end consumer.

Referring to the drawings in detail, and initially to Figs. 1-6 thereof, a specific example of a metered dose inhaler according to the present invention is adapted to be used with a canister 1 containing a pharmaceutical drug formulation to be inhaled, along with a propellant in liquid form.

The term "drug formulation" refers to a drug useful for inhalation therapy, and optionally, in combination with one or more other pharmacologically active agents, and optionally, containing one or more excipients. The term "excipient" as used herein includes chemical agents having little or no pharmacological activity (in the quantities used), but which enhance the drug formulation or the performance of the MDI system. For example, useful excipients include, but are not limited to, surfactants, preservatives, flavorings, antioxidants, and co-solvents, e.g., ethanol and diethyl ether.

Suitable drugs that are useful in inhalation therapy include, but are not limited to, analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl and morphine; anginal preparations, e.g., diltiazem; antiallergics, e.g., cromoglycate, ketotifen and nedocromil; antiinfectives e.g., cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; antihistamines, e.g., methapyrilene; anti-inflammatories, e.g., beclomethasone (for example, as the dipropionate), flunisolide, budesonide, tipredane, mometasone, and triamcinolone acetonide; antitussives, e.g., noscapine; bronchodilators, e.g., salbutamol, salmeterol, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuterol, orciprenaline, and (-)-4-amino-3,5-dichloro-.alpha.-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl] benzenemethanol; diuretics, e.g., amiloride; anticholinergics, e.g., ipratropium, atropine and oxitropium; hormones, e.g., cortisone, hydrocortisone and prednisolone; xanthines, e.g., aminophylline, choline theophyllinate, lysine theophyllinate and theophylline; and therapeutic proteins and peptides, e.g., insulin and glucagon. It will be clear to a person skilled in the art that, where appropriate, the medicaments may be used in the form of salts (e.g. as alkali metal or amine salts, or as acid addition salts), or as esters (e.g. lower alkyl esters), or as solvates (e.g. hydrates), etc., to optimize the activity and/or stability of the medicament and/or to minimize the solubility of the medicament in the propellant.
"Propellant" as used herein refers to at least one pharmacologically inert liquid with a boiling point from about room temperature (25°C) to about -25°C, and which singly or in combination exerts a high vapor pressure at room temperature. Upon actuation of the MDI system, the high vapor pressure of the propellant in the MDI forces a metered amount of drug formulation out through the metering valve. Then, the propellant very rapidly vaporizes, dispersing the drug particles. Some propellants that can be used in the present invention are low boiling fluorohydrocarbons, for example, 1,1,1,2-tetrafluoroethane, also known as "propellant 134a" or "HFC 134a," and 1,1,1,2,3,3,3-heptafluoropropane, also known as "propellant 227" or "HFC 227". Other frequently used propellants are hydrocarbons.

In embodiments, drug formulations for use in the invention may be free or substantially free of formulation excipients other than a propellant, e.g., surfactants, co-solvents, etc. Such drug formulations are advantageous since they may be substantially taste and odour free, less irritating, and less toxic than excipient-containing formulations.

Canister 1 includes a main body 1a closed at one end by a cap 1b, and both of which may be made of any suitable material, for example, aluminium or an alloy thereof. Cap 1b includes a metered dose valve 2 which may be made, for example, of aluminum and/or nylon. Metered dose valve 2 is constructed such that, upon activation, it consistently releases a fixed, predetermined mass of the drug formulation. As the formulation is forced from the container through metered dose valve 2 by the high vapor pressure of the propellant, the propellant rapidly vaporizes, leaving a fast moving cloud of very fine particles of the drug formulation. A valve stem 3 extends from metered dose valve 2 and may be made, for example, from nylon. Valve stem 3 aids in delivering the required amount of the medicament when actuated.

As shown in Figs. 1-13, a metered dose inhaler according to the present invention includes a main housing 9 which provides an internal seating 9a in the lower surface 9f thereof for seating valve stem 3, and through which the drug is delivered when canister 1 is actuated. The position of internal opening 9a is economically designed such that there will not be a significant loss in the spray when canister 1 is actuated, and which provides that an optimal plume geometry is also maintained which will provide a good dispersion path when inhaled.

Thus, main housing 9 has a generally rectangular parallelepiped body 9e with an inclined upper edge 9f, and a flared lower edge 9g. One of the side walls of body 9e includes a display window 9c for displaying an indication of the number of doses remaining, and thus providing vital information as to when to stop using the metered dose inhaler. Horizontal slots 9w (Fig. 12) are provided on the interior surfaces of two opposing walls of generally rectangular parallelepiped body 9e near the upper end thereof.

As shown particularly in Figs. 11-13, internal seating 9a is provided centrally of a lower wall 9k of body 9e adjacent the lower edge 9g, and includes a flared inlet 9h, followed by a cylindrical opening 9i in communication therewith, followed by a tapered opening 9j in communication therewith. An annular shoulder 9x is thereby provided between cylindrical opening 9i and tapered opening 9j for seating the distal end of valve stem 3. The lower end of tapered opening 9j is connected with an outlet nozzle 9b having an outlet opening 9m through a small diameter opening 9n, with outlet opening 9m and small diameter opening 9n being at an angle, for example, 45 degrees, relative to tapered opening 9j. In this manner, valve stem 3 fits within flared inlet 9h and cylindrical opening 9i to deliver the drug through outlet opening 9m of nozzle 9b.

In addition, there are four vertical guide bars 9p at the lower inside corners of main housing 9, the purpose for which will be apparent from the discussion hereafter.

Main housing 9 has a generally semi-cylindrical member 9q at the lower end thereof below lower edge 9g, which is formed by two parallel, spaced apart, generally circular walls 9r which are connected together by a curved rear wall 9s. Each circular wall 9r includes a central opening 9t and an arcuate guide slot 9d above central opening 9t, with the rotational axis of arcuate guide slot 9d being the same as that for central opening 9t. An inclined wall 9v, best shown in Fig. 12, connects front ends of circular walls 9r and extends down and outwardly there from in a manner generally parallel to the portion of lower wall 9k positioned there above.

As shown in Figs. 6 and 14-18, a generally rectangular parallelepiped shaped mouthpiece 10 is arranged to slidably fit between inclined wall 9v and the portion of lower wall 9k positioned there above. Mouthpiece 10 includes a slot or opening 10a at the upper portion thereof for insertion of nozzle 9b therein, while permitting mouthpiece 10 to move into and out of main housing 9 between inclined wall 9v and the portion of lower wall 9k positioned there above. The position of mouthpiece 10 is carefully designed with the plume geometry such that the velocity of the spray is not affected. The outer dimensions of mouthpiece 10 are designed to suit readily available spacers in the market. Hence, the design avoids spacer attachments to increase the distance the medication has to travel so the medication slows down, that is, decreases in speed, before it enters the patient's mouth.

In order to permit such translational movement of mouthpiece 10, slightly arcuate, generally semi-circular guide slots 10b are provided at the upper ends of opposite side walls of mouthpiece 10, the function of which will be explained hereafter.

As shown in Figs. 1, 2, 5, 6, and 19-22, a shutter 11 is connected with semi-cylindrical member 9q and mouthpiece 10, and functions as a dust cap and a guiding mechanism which will convert rotary motion of shutter 11 into linear motion of mouthpiece 10. Shutter 11 has a generally U-shaped configuration formed by two spaced apart, parallel side walls 11e and 11f, connected together at one end by a slightly arcuate, front connecting wall 11g. Front connecting wall 11g has horizontal serrations 11c on the front surface and a radial cut above the horizontal serrations 11 on the front surface thereof.

Each side wall 11e and 11f has a central pivot boss 11b at the inner surface that rotatably fits within a respective central opening 9t of main housing 9 so as to be rotatably mounted thereto. Each side wall 11e and 11f further includes a guide pin 11a, for example having a height of 3 mm, on the inner surface near the free end thereof. Guide pins 11a extend through respective arcuate guide slots 9d of main housing 9 and into the respective semi-circular guide slot 10b of mouthpiece 10.

When shutter 11 is moved into covering relation to the open end of mouthpiece 10, guide pins 11a force mouthpiece into main housing 9 in a sliding manner. When shutter 11 is moved down out of covering relation to mouthpiece 10, guide pins 11a guide mouthpiece 10 in a sliding movement out of main housing 9, thus providing easier access to the user.

The slotted paths of arcuate guide slots 9d are designed such that first 60° of rotational movement of shutter 11 will ensure that there will be no linear movement of mouthpiece 10 from main housing 9, thereby providing that shutter 11 does not allow mouthpiece 10 to move until it is completely opened, that is, until shutter 11 is completely free of mouthpiece 10. After this 60° of movement, mouthpiece 10 will start moving forwardly and comes out completely from main housing 9. Shutter 11 will move for a total rotational angle of about 150°. When shutter 11 is moved down, then mouthpiece 10 slides out of main housing 9 with the help of guiding slots 9d which are guided by rotary movement of shutter 11.

The construction of the dose counter assembly will now be described.

Referring first to Figs. 6 and 23-27, a dose counter casing 8 is mounted in main housing 9. Dose counter casing 8 has a generally cylindrical wall 8g closed partially by a bottom annular wall 8h having a central circular opening 8f. Bottom annular wall 8h seats on lower wall 9k of main housing 9, and is guided into a correct position by vertical guide bars 9p. Metered dose valve 2 seats on the upper surface of bottom annular wall 8h with valve stem 3 extending through circular opening 8f. Dose counter casing 8 functions as a housing for the entire counter. An upper flange wall 8i extends outwardly from the upper edge of cylindrical wall 8g and is parallel to bottom annular wall 8h. Upper flange wall 8i generally includes two opposing front and rear flange walls 8j and 8k having outer linear edges and the other two opposing side flange walls 8m and 8n having outwardly convex edges.

Opposing U-shaped, vertically oriented walls 8p and 8q which open toward each other are provided in spaced relation at the front of dose counter casing 8 and extend outwardly of cylindrical wall 8g. Opposing U-shaped walls 8p and 8q define a vertical guide slot 8d for slidably receiving a dose counter slider 5, as will be described hereafter, which can viewed through display window 9c.

Four bracket slots 8a are provided at the four corners of dose counter casing 8 within cylindrical wall 8g and extend into flange wall 8i thereat. In addition, four equiangularly arranged leaf springs 8b extend inwardly and upwardly from bottom annular wall 8h so as to extend inwardly of central circular opening 8f but positioned above central circular opening 8f. Also, two diametrically arranged locking fingers or pawls 8e are arranged to extend upwardly from the upper surface of bottom annular wall 8h and can be viewed through side windows 8c in cylindrical wall 8g

As shown particularly in Figs. 6 and 28-32, the dose counter assembly includes a dose counter rotor 7 that rotatably seats within cylindrical wall 8g of dose counter casing 8 through fixed slots 8r. Dose counter rotor 7 includes an annular cylindrical wall 7e with a circular inner opening 7d provided at the center thereof for receiving valve stem 3 of canister 1 there through. In embodiments, the total height of dose counter rotor 7 is about 4 mm.

Cylindrical wall 7e is provided with 30 lower gear teeth at the bottom edge thereof, and 30 equiangularly spaced apart, upwardly extending, internal ribs 7c on the inner surface thereof, adjacent the upper edge of cylindrical wall 7e. All internal ribs 7c are cut at the upper surfaces thereof with an angle face relative to the horizontal surface of the upper edge of cylindrical wall 7e of about 25 degrees. A helix or spiral 7a in embossed form is formed on the outer surface of cylindrical wall 7e of dose counter rotor 7. Helix 7a starts adjacent the lower edge of cylindrical wall 7e at the number "0" position, and ends adjacent the upper edge of cylindrical wall 7e at the number "30" position. A separation or relief 7f between the start and end of helix 7a is provided for the initial setup of the vertical dose counter slider 5, as will be explained hereafter. In an embodiment, relief 7f occupies an angular extent of about 20 degrees around cylindrical wall 7e.

Further, a small groove 7g is provided on the upper edge of cylindrical wall 7e, for aligning and fixing dose counter rotor 7 in dose counter casing 8 in a position such that there will not be any vertical movement of dose counter rotor 7, other than rotational motion.

With this arrangement, gear teeth 7b are engaged by locking fingers or pawls 8e of dose counter casing 8. This enables dose counter rotor 7 to move in only one direction and ensures a fixed index of one dose out of thirty doses, that is, 1/30. This arrangement can be observed through side windows 8c.

As shown particularly in Figs. 6 and 33-36, the dose counter assembly further includes a dose counter actuator 6 positioned over dose counter rotor 7 within dose counter casing 8.

Dose counter actuator 6 includes a cylindrical wall 6f partially closed by an annular bottom wall 6g having a central circular opening 6e. In this manner, canister 1 seats in the cup-shaped arrangement of cylindrical wall 6f and bottom wall 6g, with valve stem 3 extending through circular opening 6e, as shown in Fig. 5.

An upper annular flange wall 6i extends outwardly from the upper edge of cylindrical wall 6f, and an outer cylindrical rib wall 6d extends down from the underside of annular flange wall 6i in concentric, surrounding relation to cylindrical wall 6f. The height of annular flange wall 6i is less than that of cylindrical wall 6f. In addition, a portion 6k of the outer circumferential edge of annular flange wall 6i is cut-away for permitting passage of dose counter slider 5 thereby. Thirty vertical ribs 6c are formed equiangularly at the underside of annular flange wall 6i and on the outer surface of cylindrical rib wall 6d. Vertical ribs 6c are cut at the lower surfaces thereof with an angle face relative to the horizontal surface of annular flange wall 6i of about 25 degrees.

A vertical stopper 6b is provided on the lower surface of bottom wall 6g adjacent the inner edge thereof for stopping actuation of canister 1 when mouthpiece shutter 11 is closed, so as to prevent misfiring of canister 1.

Four positioning legs 6a are equiangularly provided at the outer edge of annular flange wall 6i, and are positioned in respective bracket slots 8a of dose counter casing 8 so as to rotationally fix dose counter actuator 6 relative to dose counter casing 8.

Positioning legs 6a and corresponding bracket slots 8a are carefully designed, and the clearance there between is maintained with very minimum tolerance to avoid any rotary movement of dose counter actuator 6. In this position, leaf springs 8b function as mechanical springs for upward and downward motion of dose counter actuator 6. In this regard, leaf springs 8b extend through circular inner opening 7d of dose counter rotor 7 into engagement with the lower surface of annular bottom wall 6g.

As shown particularly in Figs. 6 and 37-40, dose counter slider 5 is assembled with dose counter rotor 7. Specifically, dose counter slider 5 includes a planar first rectangular plate 5a and a planar second smaller rectangular plate 5f having a lower end connected to the upper end of first rectangular plate 5a such that first rectangular plate 5a is parallel to second rectangular plate 5f, but offset thereto. First rectangular plate 5a has a triangular cut-away section 5g at the lower edge at one side thereof.

The surface of first rectangular plate 5a facing away from second rectangular plate 5f is concave and is formed with four helical meshing ribs 5e in a helix meshing zone 5c, which as shown in Fig. 40, have a generally trapezoidal cross-sectional configuration. Helical meshing ribs 5e are designed to mesh with helix 7a of dose counter rotor 7. Two vertically spaced-apart stopper tabs 5d are provided centrally at the lower end of the opposite surface of first rectangular plate 5a.

The surface of second rectangular plate 5f facing away from first rectangular plate 5a includes a flat printing zone 5b with three vertically spaced apart flat rectangular printing areas 5b1, 5b2, and 5b3, onto which different colors are printed, in an embodiment, green in area 5b1, orange in area 5b2, and red in area 5b3.

Dose counter slider 5 is slidably received in a vertical guide slot 8d which is defined between opposing U-shaped walls 8p and 8q of dose counter casing 8, such that one of printing areas 5b1, 5b2, or 5b3 can be viewed through display window 9c. In like manner, a portion 6k of the outer circumferential edge of annular flange wall 6i of dose counter actuator 6 is cut-away for permitting passage of dose counter slider 5 thereby.

In this position, separation or relief 7f between the start and end of helix 7a of dose counter rotor 7 provides for the initial setup of the vertical dose counter slider 5, such that helix 7a of dose counter rotor 7 fits within helical meshing ribs 5e. Thus, as dose counter rotor 7 rotates, dose counter slider 5 is moved up within vertical guide slot 8d

The entire dose counter assembly of dose counter slider 5, dose counter actuator 6, dose counter rotor 7 and dose counter casing 8 is fixed between nozzle 9b and valve stem 3. One side of main body 9 is provided with display window 9c where the color indicator, that is, printing areas 5b1, 5b2, and 5b3 move upward, indicating the number of doses remaining, and thus provides vital information when to stop using the MDI.

As shown particularly in Figs. 1-6 and 41-45, a transparent top cover 4 is fixed over main housing 9 and functions to guide canister 1 in the vertical direction when it is activated. Top cover 4 has a generally rectangular parallelepiped body 4d.

Specifically, rectangular parallelepiped body 4d generally includes two opposing front and rear walls 4e and 4f having outer planar surfaces and the other two opposing side walls 4g and 4h having outwardly convex surfaces.

Top cover 4 has a bottom portion 4a fixed to main housing 9, and a top portion 4b which converges around canister 1 at its activation area. The upper edge of top portion 4b is angled, as is particularly shown in Fig. 43. Embossed strips 4c are provided at opposite sides adjacent the bottom edge of bottom portion 4b for engaging within slots 9w of main housing 9, to fix top cover 4 to main housing 9. The walls of bottom portion 4a are reduced in thickness from the walls of top portion 4b, thereby forming an inclined shoulder 4i on the outer surface of top cover 4 which seats on inclined upper edge 9f of main housing 9, as shown particularly in Fig. 1. This design will ensure that canister 1 moves exactly in a linear direction downward when activated, thus eliminating the loss of any backfire or leakage at the stem insertion point of the main housing 9. In addition, top cover 4 is in certain embodiments made up of transparent material which will enable a person to see the label claim and the brand name of the product, thus avoiding any mix-up issue at the manufacturing floor and dispensing area.

In order to assemble the MDI, dose counter rotor 7 is first fixed in dose counter casing 8. A fixed slot 8r and groove are provided in dose counter casing 8 and dose counter rotor 7, respectively. Dose counter actuator 6 is then inserted over dose counter rotor 7 such that the four positioning legs 6a are positioned in the four bracket slots 8a provided in dose counter casing 8. Dose counter slider 5 is then inserted from the lower side into vertical guide slot 8d of dose counter casing 8 such that helix 7a is assembled with helical meshing ribs 5e

This entire dose counter assembly is then inserted into main housing 9 of the device, with dose counter slider 5 facing through display window 9c of main housing 9. The filled canister 1 is then inserted therein, such that valve stem 3 is inserted into cylindrical opening 9i in communication with nozzle 9b of main housing 9. Top cover 4 is then inserted over main housing 9, which will ensure the fixed position of canister 1.

In operation, when canister 1 is activated, that is, pushed downward to provide a dose, and provided mouthpiece 10 is in the open condition, that is, not covered by shutter 11, canister 1 pushes dose counter actuator 6 down. Dose counter actuator 6 which is fixed over dose counter rotor 7 in dose counter casing 8 will cause dose counter rotor 7 to index one position.

Specifically, the angled lower surfaces of vertical ribs 6c on dose counter actuator 6 will match with the angled upper surfaces of internal ribs 7c of dose counter rotor 7. Initially, when dose counter actuator 6 is not activated, the vertical ribs 6c and 7c will match in alignment. However, when dose counter actuator 6 is activated, that is, pushed down against the force of leaf springs 8b, the two corresponding angular faces of ribs 6c and 7c will slide upon each other, and dose counter rotor 7 will move in a rotary direction. Movement of dose counter rotor 7 is defined by bottom gear teeth 7b on rotor 7. For every single activation, dose counter rotor 7 will move only one fixed pitch which is equal to one outer gear tooth 7b. The rotary indexing is strictly controlled by the two locking fingers or pawls 8e provided in dose counter casing 8.

When dose counter rotor 7 indexes for each actuation, the spiral helix 7a which is on the outer side of dose counter rotor 7 advances, which will correspondingly advance dose counter slider 5 in a vertically upwards direction. Basically, the rotary motion of dose counter rotor 7 is converted into vertical movement of dose counter slider 5. In embodiments, for every 30 actuations, dose counter slider 5 moves upwardly by 2 mm.

As discussed above, indicia such as three colors are printed on the dose counter slider 5, in an embodiment green, orange and red from the bottom up. The printing position on dose counter slider 5 is maintained such that for the first 0-90 actuations corresponding to the lowest three gear teeth 5e, the color green appears in display window 9c in main housing, for actuations 90-120 corresponding to the last two gear teeth 5e, the color orange appears in display window 9c, and further at the 120th actuation, the color red appears in display window 9c.

Those skilled in the art will be aware of modifications that can be made for an apparatus that delivers smaller or larger numbers of doses. In addition, it will be appreciated that, instead of providing colors on dose counter slider 5, numbers can be printed to indicate either the number of doses that have been delivered or the number of doses remaining to be delivered.

With the above in mind, and particularly, as to the position of the counter assembly, the entire housing assembly is placed in line with the nozzle without interfering with the jet spray. This position assures 100% indexing of the counter, and thus ensures a precise count. Further, as to the housing dimension, the entire counter size could be within the limits of 6-20 mm.

Further, as discussed above, the metered dose inhaler also prevents actuation when shutter 11 is closed, thereby preventing loss of the medicament. This is a safety feature that prevents spraying when the shutter 11 is closed.

Specifically, when shutter 11 is closed over mouthpiece 10, mouthpiece 10 is retracted into the MDI. In this position, vertical stopper 6b provided on the lower surface of bottom wall 6g of dose counter actuator 6 abuts against mouthpiece 10, so that dose counter actuator 6, and thereby canister 1, cannot be pushed down. This stops actuation of canister 1 when shutter 11 is closed, so as to prevent misfiring of canister 1. When shutter 11 is removed, so that mouthpiece 10 extends out of the MDI, dose counter actuator 6 can be moved down, since vertical stopper 6b will no longer hit mouthpiece 10.

Non-limiting examples of materials that can be used for construction of any of the components of the MDI are the polymers nylon, polycarbonate, polyolefins, Teflon, poly(methylmethacrylate), polyoxymethylene, polypropylene, acrylonitrile-butadiene-styrene, etc.

In embodiments, the MDI can and cap are made of aluminum or an alloy of aluminum, although other metals not affected by the drug formulation, such as stainless steel, an alloy of copper, or tin plate, may be used. The MDI may also be fabricated from glass or plastic. MDI canisters employed may be made of aluminum or an alloy thereof which are capable of withstanding particularly stressful coating and curing conditions, e.g. particularly high temperatures, which may be required for certain fluorocarbon polymers. The fluorinated polymer may be blended with non-fluorinated polymers such as polyamides, polyimides, polyethersulfones, polyphenylene sulfides, and amineformaldehyde thermosetting resins. These added polymers improve adhesion of a polymer coating to the can walls.

The metered dose inhaler can have part or all of its internal metallic surfaces coated with a composition that is resistent to formulation components, such as an epoxy or one or more fluorocarbon polymers, optionally in combination with one or more non-fluorocarbon polymers, for dispensing an inhalation drug formulation and a fluorocarbon propellant optionally in combination with one or more other pharmacologically active agents and one or more excipients.

The MDI canister may be coated by any means known in the art of metal coating. For example, a metal, such as aluminum or stainless steel, may be pre-coated as coil stock and cured before being stamped or drawn into the can shape. This method is well suited to high volume production for two reasons. First, the art of coating coil stock is well developed and several manufacturers can custom coat metal coil stock to high standards of uniformity and in a wide range of thicknesses. Second, the pre-coated stock can be stamped or drawn at high speeds with precision by essentially the same methods used to draw or stamp uncoated stock.

Other techniques for obtaining coated canisters is by electrostatic dry powder coating or by spraying preformed MDI canisters inside with formulations of the coating fluorinated polymer/polymer blend and then curing. The preformed MDI cans may also be dipped in the fluorocarbon polymer/ polymer blend coating formulation and cured, thus becoming coated on the inside and out. The fluorocarbon polymer/polymer blend formulation may also be poured inside the MDI cans and then drained out, leaving the insides with the polymer coat. Conveniently, for ease of manufacture, preformed MDI cans are spray-coated with the fluorinated polymer/polymer blend.

A fluorocarbon polymer/polymer blend may also be formed in situ at the can walls using plasma polymerization of the fluorocarbon monomers. Fluorocarbon polymer films may be blown inside the MDI cans to form bags. A variety of fluorocarbon polymers such as ETFE, FEP, and PTFE are available as film stock.

According to the MDI DPI Guidance Document ("Guidance for Industry, Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products," United States Food and Drug Administration, CDER, October 1998, Section III.F.2.h), the test for "Emitted Dose Content Uniformity" is an amount of active ingredient per determination not outside of 80-120% of the label drug delivery claim for more than one of ten containers, none of the determinations is outside of 75-125% of the label claim, and the mean is not outside of 85-115% of the label claim. If two or three of the ten determinations are outside of 80-120% of the label claim, none is outside of 75-125% of the label claim, and the mean is not outside of 85-115% of the label claim, an additional 20 containers should be sampled (second tier). For the second tier of testing of a batch, the amount of active ingredient per determination is not outside of 80-120% of the label claim for more than 3 out of all 30 determinations, none of the 30 determinations is outside of 75-125% of the label claim, and the mean is within 85-115% of the label claim.

Particle size measurements for aerosols released from pMDIs and DPIs are usually obtained using cascade impactors, where the aerosol cloud is drawn at a pre-determined air-flow rate through an apparatus containing a series of impaction plates or stages, arranged in such a way that particles of different sizes are collected on different stages. The individual stages can then be washed quantitatively to recover collected drug, and the mass of drug associated with each size band can be determined. Cascade impactors represent the measurement devices of choice for particle size analysis in pharmacopeias, and are recommended in guidance documents issued by regulatory authorities. The Andersen cascade impactor (ACI), multi-stage liquid impinger, and Marple-Miller impactor are the three systems most often used for particle size distribution measurements. The ACI is often a preferred device, since it divides the aerosol cloud into the largest number of fractions, allowing the particle size distribution to be examined in detail.

Inhalation devices of the present invention can be subjected to a flow resistance study. In general, the resistance to airflow of a device restricts the inspiratory flow through the DPI that can be generated by the patient, and is a predictor of patient comfort during use. Device resistance is calculated using the following equation,

Device resistance = (AP)05 X Q

where (AP) is pressure drop and Q is volumetric flow rate. Low resistance devices have resistance values less than 0.05 (cm H2O)05(L/minute), medium resistance devices have resistance values of 0.05 to 1 (cm H20)°5 (L/minute) and high resistance devices have resistance values of more than 1 (cm H20)°5 (L/minute). See A. R. Clark and A. M. Hollingsworth, "The relationship between powder inhaler resistance and peak inspiratory conditions in healthy volunteers - implications for in vitro testing," Journal of Aerosol Medicine, Vol. 6, pp. 99-110, 1993.

The device can be used with methods for pulmonary administration of drugs.

The particle sizes of a particulate (e.g., micronised) drug should be such as to permit inhalation of substantially all the drug into the lungs upon administration of the aerosol formulation and will thus generally be less than about 100 um, or less than about 20 um, in the range of about 1-10 um, or in the range of about 1-5 um.

A final aerosol formulation may contain about 0.005-10% by weight, or about 0.005-5% by weight, or about 0.01-1.0% by weight of drug, based on the total weight of the formulation.

CLAIMS:

1. A metered dose inhaler for dispensing aerosolized medication from a pressurized canister contained therein, having a mouthpiece through which a dose of aerosolized medication can pass from the canister into the mouth of a patient, the mouthpiece extending from the metered dose inhaler body for delivery of a dose and retracting into the body for storage.

2. The metered dose inhaler of claim 1, wherein the mouthpiece is extended and retracted by rotation of a shutter located at a lower portion of the body when the body is oriented vertically.

3. The metered dose inhaler of claim 2, wherein the shutter, when rotated to retract the mouthpiece, blocks passage of an aerosolized medication.

4. The metered dose inhaler of any of claims 1-3, in which a mouthpiece has a generally horizontal longitudinal axis that is perpendicular to the longitudinal axis of the body while in use, the body extending upwardly from a rear portion of the mouthpiece, and actuation of a dose is caused by pressing downwardly on a closed end of a vertically oriented canister extending beyond an upper limit of the body, further comprising a dose delivery counter within the body and in contact with the canister, moving linearly together with the canister during actuation, having:

i) a horizontal element being provided with a plurality of vertical ribs extending from its lower surface; and

ii) a horizontal ring element positioned below and in contact with horizontal element i) and being provided with: a) ribs in an inner annular edge that interact with vertical ribs in i) to produce incremental rotation for each canister actuation; and b) a spiral helix about an outer edge that incrementally moves a vertical dose counting slider with each incremental rotation;

wherein both of i) and ii) are provided with inner openings that allow a valve stem of the canister to protrude there through.

5. The metered dose inhaler of claim 4, wherein the vertical dose counting slider is provided with indicia showing the number of doses dispensed or the number of doses remaining to be dispensed.

6. The metered dose inhaler of claim 4, wherein the mouthpiece, when retracted, abuts the dose delivery counter to prevent canister actuation.

7. The metered dose inhaler of any of claim 1-6, having a body composed of a polymeric material.