Medicament respiratory delivery device and method

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MEDICAMENT RESPIRATORY DELIVERY
DEVICE AND METHOD

RELATED APPLICATIONS

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This Application is a continuation application of Ser. No. 09/950,369 filed Sep. 10, 2001 now U.S. Pat. No. 6,644,309, which is a continuation-in-part application of Ser. No. 09/879,517 filed Jun. 12, 2001, now U.S. Pat. No. 6,929,005, which is a continuation-in-part application of Ser. No. 10 09/758,776 filed Jan. 12, 2001 now U.S. Pat. No. 6,722,364, all three of which are herein incorporated by reference.

FIELD OF THE INVENTION

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This invention relates to medicament respiratory delivery devices, including pulmonary, intranasal and buccal respiratory delivery devices, which releases and delivers on demand a controlled unit dose of aerosolized medicament to the respiratory system of a patient and method of delivery. 20

BACKGROUND OF THE INVENTION

Inhalers and atomizers are now commonly used primarily to deliver various liquid medicaments via the patient's or 25 user's nose or mouth. As used herein, "medicament" includes any powder or liquid medicament, drug or vaccine or combinations thereof which may be administered from an respiratory delivery device through the user's nose or mouth, sometimes referred to herein as a medicament res- 30 piratory delivery device. More recently, the prior art has proposed unit dose disposable powder medicament delivery devices, such as disclosed in U.S. Pat. No. 5,215,221, wherein a predetermined quantity or unit dose of a powder medicament is sealed in a reservoir formed between opposed 35 thermoplastic sheets and expressed or delivered by application of manual force to a thermoformed blister which, upon activation, breaks a burstable seal between the sheets at the entrance to the reservoir and fluidizes the powder medicament in the reservoir through a delivery tube. The sealed 40 delivery tube is cut prior to use.

There are several considerations affecting the design and efficacy of medicament respiratory delivery devices. First, it is important to ensure that a predetermined quantity or dose of medicament is consistently delivered to the user with each 45 application. Second, because respiratory therapy often requires numerous applications, the cost of providing the dosage should also be considered. Thus, it is desirable that the medicament respiratory delivery device consistently express substantially all of the medicament to the user and 50 that the delivery device is not susceptible to user error in operation. Third, it is important that the medicament be properly disbursed or entrained in the conveying fluid. Further considerations include the operating complexity, cost of the device, portability and size of the delivery device. 55 It would also be desirable in certain applications to provide a reusable delivery device with a disposable standard medicament cartridge containing a unit dose of medicament which can be easily handled and replaced in the delivery device by the user without error. In other applications, a 60 disposable delivery device is desirable.

Further, it would be desirable for a respiratory delivery device to deliver a controlled unit dose of an aerosolized medicament on demand. That is, it would be desirable to be able to charge or pressurize the medicament respiratory 65 delivery device prior to use, such that the patient does not have to simultaneously manipulate the pressure delivery

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means, as by compressing a bulb or syringe, with the mouth or nosepiece in the patient's mouth or nose, while inhaling the aerosolized medicament. This can be difficult for some patients to accomplish and may result in poor or partial delivery of the medicament.

The medicament respiratory delivery device of this invention provides a reproducible, high level of clearance of medicament or emitted dose from a replaceable cartridge, wherein a manually actuatable fluid pressure delivery device may be charged prior to use and then released on demand to deliver a controlled unit dose of an aerosolized medicament to the respiratory system of the patient.

SUMMARY OF THE INVENTION

As set forth above, the medicament respiratory delivery device of this invention may be utilized for pulmonary, intranasal, and buccal respiratory delivery of medicaments, drugs or vaccines and various combinations thereof. The medicament respiratory delivery device of this invention includes a medicament housing including a chamber having a chamber inlet and preferably a generally coaxially aligned chamber outlet, a medicament cartridge is preferably located within the housing chamber having opposed ends, a passage through the cartridge through the opposed ends generally coaxially aligned with the chamber inlet and outlet of the housing, a medicament in the cartridge passage and a burstable membrane sealing the passage preferably at both ends of the cartridge having a burst pressure of less than 10 atmospheres. The medicament respiratory delivery device further includes a manually actuatable fluid delivery device having an outlet in fluid communication with the chamber inlet for delivery of fluid under pressure to the chamber and a valve located between the outlet of the fluid delivery device and the chamber inlet including a valve inlet in fluid communication with the outlet of the fluid delivery device and an outlet in fluid communication with the chamber inlet of the medicament housing.

Upon actuation of the manually actuatable fluid delivery device, fluid is delivered under pressure to the valve, thereby charging the medicament respiratory delivery device for use. Then, upon opening of the valve, fluid is delivered under pressure to the inlet of the chamber containing the cartridge, thereby rupturing the burstable membranes of the cartridge and expressing the medicament through the chamber outlet. In the preferred embodiment, the manually actuatable fluid delivery device is actuatable to maintain the fluid pressure at the outlet, prior to opening of the valve, to permit the user to release the manually actuatable fluid delivery device and insert the housing outlet into the nose or mouth.

The medicament respiratory delivery device of this invention thereby separates the charging or pressurizing function from the use function. That is, the medicament aerosol delivery device of this invention may be utilized by a patient to first "arm" or pressurize the valve inlet and then deliver fluid under pressure to the housing chamber containing the cartridge by opening the valve. Thus, for example, the patient may first arm the medicament respiratory delivery device of this invention by manipulating the pressure delivery device to pressurize a chamber at the valve inlet, then turn the device to receive the mouthpiece or nosepiece in the user's mouth or nose and then open the valve to deliver a controlled unit dose of an aerosolized medicament to the respiratory system of the patient through the nose or mouth. This simplifies the operation and use of the device to 3

minimize user error and consistently deliver a predetermined quantity or dose of medicament to the patient's respiratory system.

As will be understood by those skilled in this art, various fluid delivery devices and valves may be utilized in the 5 medicament respiratory delivery device of this invention. For example, the fluid delivery device may include a collapsible bulb which communicates with a pressure chamber through a one way valve having an outlet in communication with the valve inlet. However, in a preferred embodiment of 10 the medicament respiratory delivery device of this invention disclosed herein, the manually actuatable fluid delivery device includes a tubular pressure member having an outlet and a plunger or stopper received in the tubular pressure member in sealed relation which is manually reciprocable in 15 the tubular pressure member toward the pressure member outlet. The manually actuatable fluid delivery device may be a conventional syringe preferably having finger grips and a plunger and stopper assembly, such that the patient can hold the barrel and manipulate the plunger with the patient's 20 thumb. Thus, upon movement of the plunger, the stopper is moved in sealed relation toward the syringe outlet, pressurizing the fluid, preferably air, at the syringe outlet. Opening of the valve at the pressure member outlet thus releases or expresses the fluid into the housing chamber containing the 25 cartridge, rupturing the burstable membrane and delivering the medicament to the outlet of the housing as described. In the preferred embodiment, the plunger and stopper assembly and tubular barrel include cooperative stop members which releasably retain the stopper in the barrel when the stopper 30 is moved in the tubular barrel to generate sufficient pressure at the syringe outlet to rupture the burstable membranes. In the disclosed embodiment, the valve is a conventional Schraeder valve operable at pressures of 10 atmospheres or less having a valve stem extending toward the housing, such 35 that movement of the housing toward the manually actuatable fluid delivery device opens the valve and delivers the fluid under pressure to the housing chamber inlet. In the preferred embodiment, the housing includes a bar or finger in the inlet, such that the finger or bar engages the valve stem 40 when the housing is moved toward the manually actuatable fluid delivery device or syringe; however, the valve stem may also engage directly against the burstable membrane at the inlet of the cartridge. Alternatively, the valve stem may extend into the syringe barrel for engagement by the stopper 45 as described further below. As will be understood, however, the valve may be any suitable valve, preferably a manually actuatable valve as discussed further below.

In the disclosed embodiment of the medicament respiratory delivery device of this invention, the plunger comprises 50 two telescopic tubular members including a plunger affixed to the stopper and a tubular piston housing which telescopically receives the plunger and the plunger is resiliently biased by a coil spring or the like. The plunger and stopper assembly is assembled by inserting the plunger into the 55 tubular piston housing, compressing the spring and locking the members together by a detent on the plunger which is received in a detent pocket on the tubular piston housing with the spring partially compressed. Then, upon opening of the valve, the sudden drop in pressure allows the spring to 60 drive the stopper to the outlet of the syringe barrel, sweeping the remaining fluid in the barrel through the valve.

As set forth above, in the preferred embodiment of the medicament respiratory delivery device of this invention, the manually actuated fluid delivery device is actuatable to 65 maintain the fluid pressure at the outlet prior to opening of the valve to permit the user to release the fluid delivery

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device and insert the medicament housing outlet into the nose or mouth prior to opening of the valve. In the disclosed embodiment, wherein the manually actuatable fluid delivery device comprises a tubular pressure member, such as a syringe barrel, and a plunger or stopper, interlocking stop members are provided on the syringe barrel and the plunger and stopper assembly which allow the user to fix the plunger when the pressure at the syringe outlet is sufficient to rupture the burstable membranes of the medicament cartridge. This allows the user to fix the stopper in the syringe barrel and maintain the pressure at the syringe barrel outlet while turning the device to receive the outlet of the medicament housing in the nose or mouth prior to opening the valve. In the disclosed embodiment, the valve is a conventional Schraeder valve having a projecting valve stem and the medicament housing is moveable relative to the manually actuatable fluid delivery device to depress the valve stem and open the valve.

The cartridge for the medicament respiratory delivery device of this invention is preferably simple in construction, inexpensive and disposable, such that the delivery device is reusable by inserting a new cartridge in the housing chamber following each use. However, the cartridge may be eliminated in a nonreusuable delivery device wherein the burstable membranes are provided at the inlet and outlet to the housing chamber. In the preferred embodiment of the medicament respiratory delivery device of this invention, the medicament cartridge includes a body having opposed ends, a passage through the body and through the opposed ends, a medicament stored in the passage and burstable or pierceable membranes covering and sealing the passage at the opposed ends of the body. In the preferred embodiments, the opposed ends of the cartridge body surrounding the passage are convex and the burstable membranes are stretched taut over the convex opposed ends and bonded thereto, sealing the passage. In the disclosed embodiment, the opposed ends of the body are frustoconical surrounding the passage and the membranes comprise a thin polyolefin film heat-sealed or fused to the opposed frustoconical ends of the body. The term polyolefin is understood to mean a polymer containing olefin units such as, for example, ethylene, propylene or 1 -butene units or any other alpha-olefin. Polyolefin as used herein includes polyethylene, polypropylene, ethylene-.alpha, olefin copolymer, wherein the alpha olefin having from 3 to 20, preferably 4 to 8 carbon atoms, polyolefin copolymers made by polymerizing olefins in the presence of a metallocene catalyst, ethylene-vinyl acetate copolymer, ethylene-ethyl acrylate copolymer, and ethylene-methyl acrylate copolymer. In particular, it is desirable to use polyethylene, such as low-density, linear-low-density, very-lowdensity, medium-density, or high-density polyethylene, or polypropylene, such as a polypropylene homopolymer, ethylene-propylene copolymer, or ethylene-propylene block copolymer.

In one preferred embodiment, the polymeric films which form the burstable membranes are preferentially or uniaxially oriented polyolefin films, preferably oriented polyethylene films, angularly related, wherein the films oriented on the opposed ends of the cartridge are most preferably oriented at approximately right angles. It has been found by the applicant that burstable membranes formed of preferentially or uniaxially oriented polyolefin film, most preferably polyethylene film, wherein the films are oriented at approximately right angles, results in improved delivery of the medicament from the body chamber of the delivery device to the respiratory system of the user and results in a consistently greater emitted dose. Polyolefin films can be 5

oriented by drawing in one or both mutually perpendicular directions in the plane of the film to impart strength thereto using methods known in the art. Oriented polyolefin films include machine direction and transverse direction orientation. Oriented polyolefin films include uniaxially or biaxi- 5 ally oriented films, with uniaxially films being preferred having a draw ratio of at least 1.2. Uniaxially-oriented films have properties to their advantage for use as the burstable membranes, including relatively high stiffness, as indicated by the tensile modulus in a particular direction, usually the 10 machine direction, compared to the transverse direction. Properties of the oriented polyolefin film can be dependent to a certain degree on the particular process conditions under which the polyolefin film was manufactured. For example, a stiffer film with lower transverse burst pressure properties 15 would result from an orientation process incorporating a larger machine direction orientation draw ratio. Thus, oriented polyolefins films can be tailored to provide an appropriate burst pressure property within a preferred film thickness range. 20

Based upon computer modeling by the applicant, consistently greater dosing is believed to result from turbulence or "turning" of the delivery fluid through the passage of the cartridge containing the medicament where preferentially oriented polyolefin membranes are used oriented at approxi- 25 mately right angles on the opposed ends of the cartridge. Prototype testing indicates that the burstable membranes at the opposite ends of the cartridge in the delivery devices of this invention rupture nearly simultaneously using only a modest pressure, e.g., less than 5 atmospheres. Where the 30 membranes are preferentially or uniaxially oriented and perpendicular, the membranes each rupture in a slit near the center along the axis of the oriented films at approximately right angles to one another. This requires the fluid, such as a gas, to turn as the fluid is rapidly transmitted through the 35 passage, entraining the medicament and expressing the entrained medicament through the slit formed in the second membrane. It has been found by the applicant that generally perpendicular orientation of the preferentially or uniaxially oriented films oriented at right angles resulted in an emitted 40 dose of about 97%.

In another preferred embodiment, the burstable membranes are formed of a cast polyolefin copolymer of polyethylene and polyethylene methylacrylate copolymer film having a thickness of about 0.5 mil, wherein the films are 45 stretched taut over the passage and heat sealed or fused to the opposed ends of the cartridge. Where the burstable membranes are formed of preferentially or uniaxially oriented polyethylene film, the film preferably has a thickness of about 1 mil. However, it is believed that the burstable 50 membranes may also be formed of other polymers including, for example, polypropylene, acetate, polycarbonate, etc., wherein the film is preferably scored or embossed to reduce the required gas rupture pressure, thus having a rupture pressure of between 1.2 and 10 atmospheres, more 55 preferably less than 5 atmospheres and most preferably between 1.5 and 4 atmospheres. Medicament cartridges employing such low burst pressure films allow for use of simple, manually actuated, pressurization mechanisms as described below. In the preferred embodiment of the car- 60 tridge for a medicament delivery device of this invention, the medicament passage or reservoir is generally cylindrical and the cartridge body is also generally cylindrical. An annular groove may be provided at the mid-portion of the body for ease of handling. 65

As disclosed in the above-referenced co-pending application, U.S. Ser. No. 09/879,517, the medicament cartridge

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utilized in the medicament respiratory delivery device of this invention may be formed by injection molding a generally cylindrical cartridge body having convex end portions and a passage through the end portions. The method then includes applying a thin burstable polyolefin sheet over one end, preferably by stretching a polyethylene sheet over the end and heat bonding the sheet to the convex end of the cartridge body, sealing the first end. The medicament may then be inserted through the open end of the passage and the second end is then sealed as described. Based upon computer modeling by the Applicant, the highest medicament delivery rate is achieved using one burstable polyolefin membrane at the exit of the delivery device. This can be accomplished by the medicament delivery device of this invention by utilizing the valve stem or another piercing member to pierce the burstable membrane at the inlet prior to or during actuation of the pressure member. However, in the disclosed preferred embodiment of the medicament respiratory delivery device, the opening of the valve substantially simultaneously bursts both the inlet and outlet membranes avoiding any loss of medicament through the inlet membrane during use.

The preferred embodiments of the medicament delivery device of this invention are particularly, but not exclusively, adapted for respiratory delivery including pulmonary, intranasal or buccal medicament delivery of a powder medicament, wherein the patient's inspiratory flowrate is not the driving force or pressure behind the aerosolization of the powder medicament. The powder is dispersed by fluid pressure that ruptures the membranes on the opposed ends of the cartridge, creating a substantially instantaneous fluid stream through the cartridge, entraining the powder particles into the fluid, which disperses the medicament to the respiratory system of the patient. This allows for less dependence of the aerosolization of medicament on a patient's inspiration rate. As will be understood, however, the medicament respiratory delivery device of this invention, particularly including the cartridge, can also be utilized for liquid medicament delivery.

Other advantages and meritorious features of the medicament respiratory delivery device of this invention will be more fully understood from the following description of the preferred embodiments, the claims and the appended drawings, a brief description of which follows.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an exploded perspective view of one embodiment of the medicament respiratory delivery device of this invention;

FIG. 2A is a partially cross-sectioned side view of one embodiment of the plunger assembly illustrated in FIG. 1 prior to assembly;

FIG. 2B is a side cross-sectioned view of the plunger assembly shown in FIG. 2A following assembly;

FIG. 3 is a side partially cross-sectioned view of the medicament respiratory delivery device shown in FIG. 1 in the "unarmed" state;

FIG. 4 is a side partially cross-sectioned view of the medicament respiratory delivery device shown in FIGS. 1 and 3 in the "armed" state;

FIG. 5 is a side partially cross-sectioned view of the medicament respiratory delivery device shown in FIGS. 1, 3 and 4 during expressing of the medicament in the medicament cartridge;

FIG. 6 is a side partially cross-sectioned view of the medicament respiratory delivery device shown in FIGS. 3 to 5 following delivery of the medicament;