Deep lung alveolar aerosol targeted drug delivery

An aerosol inhalation device assembly for diagnostic and therapeutic use for deep lung alveolar aerosol targeted drug delivery includes a nebulizer for generating an aerosol containing droplets of a liquid. The nebulizer has a pressurized gas inlet and a nebulizer outlet. An inhalation chamber is in fluid communication with the nebulizer outlet. The inhalation chamber is defined by at least one sidewall. An inhalation mouthpiece assembly is in fluid communication with the inhalation chamber and extends outwardly from the at least one sidewall of the inhalation chamber. A filter assembly is in fluid communication with the inhalation chamber. The filter assembly includes a filter medium. An exit port is in direct fluid communication with the filter assembly. A method of using the nebulizer is also provided.

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to a drug and device combination, and, in particular, to a drug and device combination for administering an aerosolized medication to the lungs.

Description of the Related Art

Aerosol inhalation equipment such as nebulizers are often used in medical facilities for generating aerosol mists for diagnostic and therapeutic procedures. The mists can originate from liquids, suspensions, colloids, nano-colloids or nano- or micronized dry powders. Historically, these devices were solely used in hospitals but now some can be used in the home and include Metered Dose Inhalers (MDIs for patients with asthma or re-current bronchospasm.) Some patients with asthma, especially during severe episodes, do require nebulizer treatment at home but these devices are cumbersome and “continuous medication feed” therapy is not presently available in the home care setting.

Whether in the home or hospital, a metered dose is important because the therapeutic agents delivered (bronchodilators in asthma to congestive heart failure drugs such as VIP) are highly active biologically and dose must be controlled to impart precision and titration in the therapeutic or clinical effect seen especially when the patient is in home care setting. Such devices are especially useful, such as, for example, in pulmonary therapy for severe bronchospasm as in asthma, infectious diseases such as pneumonia (bacterial or fungal includingMycobacterium tuberculae), and vasodilators of the venous circulation systemically or within the pulmonary tree. They may be useful for introducing radioactive vapors or for special receptor binding agents used for diagnosing diseases. Typically, when devices have been developed for diagnostic use with radioactive materials, they are not used for therapeutic use because diagnostic devices require special handling, lead encasement for example, and a complex design compatible with safe uses of radioactive material. Diagnostic devices are typically designed for single application in hospitals or other medical facilities, where the use can be controlled. Diagnostic devices must prevent radioactive contamination to other caregivers and patients and in the physical area of treatment (room or corridor), and therefore route expelled air through a filter to prevent radioactive particles from exiting the device into the atmosphere. A key difference between diagnostic devices and drug delivery nebulizers is that the exhaled air path in drug delivery nebulizers is not controlled for drug delivery devices; while the purpose of controlling air flow in diagnostic radioactive agent delivery is to reduce contamination but not to optimize drug delivery. Another key difference is that residual volume can be higher than expected in diagnostic devices because the diagnostic devices are single use devices containing radioactive substances and therefore must be disposed immediately after use or within 30 minutes after the diagnostic procedure is complete, whereas drug delivery nebulizers can be reused.

To date, aerosol drug delivery has focused on pressurized cans or metered inhalers. Nebulizers used with an air pump have typically only been used for severe acute exacerbations of symptoms or where bronchospasm makes inspiration difficult. For conditions where expiration is reduced or restricted such as in asthma acutely and in chronic obstructive pulmonary disease (“COPD”) or emphysema, nebulizers are used acutely but over a longer period than one or two puffs used to relieve symptoms of asthma. In some cases, the nebulizers maybe used from minutes to hours until blood oxygen returns to normal and remains at normal levels. Especially in these cases where blood oxygen has fallen, the inhaled vapor should contain a “high payload of drug” per inspired breath to achieve the desired therapeutic effect. Delivering drugs under low-pressure conditions, by contrast, is difficult, patient pulmonary status dependent, and maybe ineffective. MDIs develop pressures up to 50 pounds per square inch upon exit at the nozzle (“psi”) to be effective and are in part dependent of the inhalation pressure or inspiration “vacuum” generated by the patient. Because inhalation pressure is low upon inhalation via a spacer for example and is dependent on the patient's lung capacity, parameters such as droplet size for aqueous and/or non-aqueous liquids and particle size for dry powders are very important to achieve a therapeutic effect. Furthermore, positive pressure MDIs effectively “blow” the medication into the nasopharynx with a high fraction of the dose adhering to the mucosal wall of the mouth and upper airway. Accordingly, the medication does not reach the lungs.

With the advent of resistant bacterial organisms, the improvements in treatment of diseases with high morbidity, such as idiopathic and or primary pulmonary hypertension, cystic fibrosis, persistent primary pulmonary hypertension, and systemic diseases such congestive heart failure with lung involvement, delivery of medications and/or drugs either as small molecules or proteins or peptides or polysaccharides or mucopolysaccharides is important. The aerosol drug delivery method offers advantages over the oral route of administration. Many highly effective agents such as those mentioned above cannot be given orally due to their acid labile properties; or because they are poorly tolerated when given by the intramuscular route. The intravenous route requires hospital care or attentive outpatient care and should be used only by nurses or those skilled or schooled. Pulmonary drug delivery is needed because it could be safe and effective if doses can be controlled and delivered properly.

The diseases where topical administration to the lung is associated with a more positive therapeutic outcome or therapeutic benefit include pneumonia, tuberculosis and cystic fibrosis where there is excessive mucous clogging the passages or bronchioles of the lung. For cystic fibrosis, where there is excess mucous clogging the airways or bronchioles of the lung, direct pulmonary treatment is the most effective therapy.

For aerosol drug delivery, therapies can be viewed simply and naively as topical therapy, but when droplet size is well-controlled and its distribution is homogenous, it can be improved to treat diseases requiring deep lung and/or alveolar targeted delivery. In the present case, deep lung delivery refers to penetration into the small airways of the lung typically ranging between 2-4 microns in diameter. For targeted alveolar drug delivery, droplets should be less than 2 microns, and preferably, less than about 1.1 microns but above 0.5 microns. In each case, the lung should be equally affected with no “dead” spots upon scanning or “clumping” in the larger bronchioles. The device ideally should deliver an even intra-pulmonary distribution of the medication.

For aerosol drug delivery, especially for deep lung or targeted alveoladelivery, it would be beneficial to provide a multi-use, refillable, and re-useable portable aerosol inhalation device that targets the deep lung and alveolar surfaces and that can be used outside of a medical facility, at home or under supervision in a chronic care facility, such as a nursing home. Further, the device should filter the exhaled air and have low residual volumes to prevent contamination or inadvertent exposure, especially with antibiotics, since many people and caregivers have circulating antibodies and can experience an allergic reaction to such chemicals; typically this is seen with penicillin. Still further, the device should have unique ports for placing the medication into an aerosolizing chamber, with minimal loss or inadvertent exposure, more than once and for the device to allow disassembling for cleaning when required and re-use.

SUMMARY OF THE INVENTION

This Summary is provided to introduce a selection of concepts in a simplified form that is further described below in the Detailed Description. This Summary is not intended to identify all key features or all essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter.

In one embodiment, the present invention is an aerosol inhalation device assembly for therapeutic use for deep lung alveolar aerosol targeted drug delivery and includes a nebulizer for generating an aerosol containing droplets of an aqueous and non-aqueous liquid. The nebulizer has a pressurized gas inlet, a nebulizer outlet, and a longitudinal axis extending between the pressurized gas inlet and the nebulizer outlet. An inhalation chamber is in fluid communication with the nebulizer outlet. The inhalation chamber is defined by at least one sidewall. The inhalation chamber extends along the longitudinal axis. An inhalation mouthpiece assembly is in fluid communication with the inhalation chamber and extends outwardly from the at least one sidewall of the inhalation chamber. The inhalation mouthpiece assembly extends at an angle relative to the longitudinal axis. A filter assembly is in fluid communication with the inhalation chamber and extends along the longitudinal axis. The filter assembly includes a filter medium. An exit port is in direct fluid communication with the filter assembly and extends along the longitudinal axis.

Further, the present invention provides the aerosol inhalation device described above and a medication supply device containing inhalation medication, the medication supply device having a connector configured to mate only with the aerosol inhalation device. The mated connectors allow for continuous administration of medication without interruption.

Additionally, the present invention provides a method of inhaling a nebulized medication comprising the steps of providing the nebulizer assembly, and the medication supply device described above; connecting the medication supply device to the injection port; injecting a medication from the medication supply device, through the injection port and into the nebulizer; injecting a low pressurized gas such as 50 psi of 20-26% oxygen and room air at a rate of between about 8 and about 12 liters per minute into the pressurized gas inlet, generating an aerosol of the medication, the aerosolized medication traveling from the nebulizer to the inhalation chamber; inhaling the aerosolized medication through the inhalation mouthpiece assembly and simultaneously trapping aerosolized medication not being inhaled in the filter medium; and exhaling through the inhalation mouthpiece assembly, such that exhaled air travels through the inhalation chamber and the filter medium to the exit port for discharge to the atmosphere.

DETAILED DESCRIPTION

In the drawings, like numerals indicate like elements throughout. Certain terminology is used herein for convenience only and is not to be taken as a limitation on the present invention. The terminology includes the words specifically mentioned, derivatives thereof and words of similar import. As used herein, the term “distal” defines a direction away from a user of the inventive device and the term “proximal” finds a direction closer to the user of the inventive device. Also, unless otherwise defined or used herein, the term “liquid” includes aqueous based solutions, oil based solutions, oil/water mixes, emulsions, suspensions, colloids, and other solutions that use a liquid as a base or ingredient.

Additionally, the term “or” is intended to mean an inclusive “or” rather than an exclusive “or”. That is, unless specified otherwise, or clear from context, “X employs A or B” is intended to mean any of the natural inclusive permutations. That is, if X employs A; X employs B; or X employs both A and B, then “X employs A or B” is satisfied under any of the foregoing instances. Also, the articles “an” and “an” as used in this application and the appended claims should generally be construed to mean “one or more” unless specified otherwise or clear from context to be directed to a singular form.

The use of figure numbers and/or figure reference labels in the claims are intended to identify one or more possible embodiments of the claimed subject matter to facilitate the interpretation of the claims. Such use is not to be construed as necessarily limiting the scope of those claims to the embodiments shown in the corresponding figures.

Referring now toFIGS. 1A-3, a nebulizer device100according to a first exemplary embodiment of the present invention is shown. Nebulizer device100generates an aerosol of an aqueous and/or non-aqueous liquid or powder medication for inhalation by a user. The medication is inhaled so that the medication is deposited in the user's lungs for diffusion into the alveolar and in some cases for quick absorption by the user's body—primarily intended to affect the pulmonary vasculature. Formulations such as aqueous, oils and emulsions can be delivered by the device described herein.

Exemplary medication can be a cardiovascular therapeutic agent, such as, for example, phentolamine, an alpha-1 antagonist and those of the same class including enantiomeric forms; sildenafil or other phosphodiesterase 5 inhibitors including enantiomeric forms; prostaglandins, prostacyclins, and prostanoids, including iloprost; nitrates, or peripherally-acting vasodilator agents such as hydralazine and related congeners, or those agents known to affect nitric oxide formation in vascular smooth muscle; nifedipine and related congeners of the slow channel calcium class or those agents known to affect calcium channels in vascular smooth muscle; and endogenous biologic products such as vasoactive intestinal peptide (“VIP”), glucagon and insulin; a pulmonary agent, such as, for example albuterol, terbutaline, or salmeterol, all classified as beta-adrenergic agonists and their enantiomeric forms; ipratropium, or water soluble anti-cholinergic agents; an endocrine agent, such as, calcitonin; α1 antitrypsin or protease enzymes and or their inhibitors; an anti-infective agent, such as, for example, aztreonam; anti-tuberculosis agents such as streptomycin; macrolide antibiotics such as those of the erythromycin class; and antibiotics such as those of the aminoglycoside class such as tobramycin which has been approved for use by inhalation by the Food and Drug Administration but not with this device; or other suitable medications including but not limited to medications that inhibit prostaglandins and cyclo-oxygenases; mucolytic agents such as acetyl cysteine; anti-inflammatories of the muco polysaccharide class also known as heparin, including those referred to as “low molecular weight heparin”.

Nebulizer device100includes a low pressurized gas inlet102located at a bottom of nebulizer device100. A nebulizer110is in fluid communication with gas inlet102. Pressurized gas from gas inlet102flows through nebulizer110and nebulizes the medication inside nebulizer110for inhalation by the user. Liquid medications can be in the form of particle containing fluids, including oils, water-based liquids, and colloidal systems including nano-emulsions or micro-emulsions, and liposomes.

An exemplary nebulizer110can be a swirling nebulizer, such as, for example, the SWIRLER®, manufactured by Amici, Inc. of Spring City, Pa., or any of the nebulizer technologies disclosed in U.S. Pat. No. 5,603,314, issued on Feb. 18, 1997, U.S. Pat. No. 5,611,332, issued on Mar. 18, 1997, and U.S. Pat. No. 5,630,409, issued on May 20, 1997, although those skilled in the art will recognize that other types of nebulizers can be used without departing from the scope of the present invention.

In an exemplary embodiment, nebulizer110can generate aerosol particles having a mean droplet size of about 2.4 microns. In an alternative exemplary embodiment, nebulizer110can generate aerosol particles having a mean droplet size of about 1.4 microns. In still another alternative exemplary embodiment, nebulizer110can generate aerosol droplet or liquefied particle having a mean droplet size of about 0.7 microns. In yet another exemplary embodiment, about 80% of aerosolized droplets generated by nebulizer110have a diameter of about 1 micron or less.

In another embodiment, nebulizer110is able to generate particle sizes in a range of between about 1 micron and about 2.4 microns. Further, the efficiency of nebulizer110generates numerous small particles that are suitable for alveolar inhalation. The small size of the nebulized particles, in combination with the large amount, combines to form high level of obscuration within an inhalation chamber120. By way of example, obscuration can be thought of as being the opposite of the transmittance, with the percentage of obscuration added to the percentage of transmittance being equal to 100 percent.

Obscuration is a relative measurement of the light lost relative to the intensity of light emitted and can be measured by the amount of light (in photons) hitting a detector from a light source. The obscuration can also be an indication of the concentration of a nebulized sample because the more particles or the more volume is taken by the sample, the less photons will make it to the detectors. Obscuration can be viewed as “payload” of the active ingredient. While the obscuration feature is known, obscuration is typically associated with non-pressurized nasal spray in the treatment of allergic rhinitis.

By way of comparative example, for nasal sprays, droplets are larger than 10 microns and obscuration should be high. For deep lung delivery, however, a droplet size of 10 microns would not penetrate or be carried down into the bronchial wall. For nebulizer device100, high obscuration (>25% as measured by a Malvern Instrument SprayTec or equivalent) can be associated with small droplets size where about >75% of the droplets are below about 1 micron under low pressure (less than about 50 psi). The pressure insensitivity of the droplet/size obscuration relationship is important because now medications could be given effectively to patients with intake restrictive bronchiole obstructive diseases or where there is increased pulmonary bronchial resistance due to excessive mucous. Also but more importantly, the low-pressure delivery prevents or reduces the amount of drug adhering to the nasopharynx preventing lung penetration.

In an exemplary embodiment, a nebulized fluid has an obscuration value of greater than about 25 and, in a further exemplary embodiment, between about 36.7 and about 42, with about 10% of the nebulized particles having a diameter of about 0.41 microns or less; about 50% of the nebulized particles having a diameter of about 0.65 microns or less; and about 90% of the nebulized particles having a diameter of about 1.4 microns or less. The narrow distribution and homogeneity of droplet size is an attribute of this method of aerosolizing. If the distribution of droplet size was “wide” or extended in a “multiple of the mean value”, then deep lung therapy or alveolar delivery could not be achieved; the dose to the target site of action would be lower and imprecise. Such “narrow” or homogeneous distribution patterns to the degree described herein have only been seen for nebulizer based methods using a nebulizer similar to nebulizer110and not for other non-sonically based nebulizers. SeeFIG. 4, which shows an exemplary graph of average particle size distribution according to nebulizer110. The steep slope of the sigmoid curve is an indication of the homogeneity of the droplet sizes.

In still another embodiment, nebulizer110is able to generate particles wherein less than about 10 percent of the generated droplets have a diameter of less than about 1.0 microns and less than about 10 percent of the generated droplets have a diameter of greater than about 1.4 microns, meaning that about 80 percent of the generated particles have a diameter between about 1.0 microns and about 1.4 microns. The lower value of about 1.0 microns is important because droplets smaller than about 1.0 microns, and typically, less than about 0.5 microns, tend to be not absorbed by the lungs during inhalation, but instead are exhaled from the patient while particles greater than about 1.4 microns are too large to reach the alveoli.

The relationship between droplet size (between about 1.0 microns and about 1.4 microns) and obscuration (above 36.7) are ideal parameters for deep lung delivery and alveolar target delivery of drugs or biologics or antibiotics where either local or systemic treatment is required.

Inhalation chamber120is located vertically above and in fluid communication with nebulizer110, coaxially along a longitudinal axis104with air inlet102and nebulizer110. Inhalation chamber120is formed from at least one sidewall122. As shown in the figures, inhalation chamber120has a generally tubular configuration, although those skilled in the art will recognize that inhalation chamber120can have other configurations as well. Further, inhalation chamber120has only a first (vertical) exit to an exit port170and a second (side) exit to an inhalation mouthpiece connector130. Exit port170is generally “blocked” by a filter assembly160such that, in the absence of the user exhaling through inhalation mouthpiece connector130, nebulized liquid from nebulizer110can only directly travel from inhalation chamber120to inhalation mouthpiece connector130. This is in contrast to the device disclosed in U.S. Pat. No. 6,412,481, which also includes a corrugated conduit114opposite from a mouthpiece124that can fill with aerosolized liquid, lowering the density and, thus, the obscuration of the aerosolized liquid in the device, resulting in lower dosages of medication to a patient. Because, with present device100, the nebulized liquid can only travel to inhalation mouthpiece connector130, the nebulized liquid cannot be dispersed to other locations, resulting in the higher obscuration values discussed above.

The intake gas can be from a pressurized system or portable nebulizer compressor commonly found in hospitals or nursing homes or medical devices suppliers where a prescription can be written, but it can also be supplied by hand, such as, for example, in the squeezing repeatedly of a manual resuscitation bag.

While, in an exemplary embodiment, the inhalation chamber120is fixedly connected to nebulizer110, such as, for example, by sonic welding, those skilled in the art will recognize that major elements of nebulizer device100can be releasably connected to adjacent elements such that elements can be removed for replacement and/or cleaning. As shown, for example, inFIG. 1B, inhalation chamber120can be releasably connected to nebulizer110, such as, for example, by a threaded connection. Such a threaded connection permits nebulizer110to be cleaned between uses.

In an alternative embodiment of a nebulizer210, shown inFIG. 2, nebulizer210includes female threaded connection212that can be releasably connected to a mating male connection (not shown) on inhalation chamber120and a deflector dome214of nebulizer210can be releasably removable from the interior of bowl218for further cleaning. Such cleaning ability allows for re-use of nebulizer210.

Referring back toFIG. 1A, in an exemplary embodiment, the interior wall of inhalation chamber120is constructed from a material, such as, for example, a hydrophobic material that has a low surface tension such that any nebulized medication that may hit the interior wall tends to vertically slide down the wall and back into nebulizer110for re-nebulization. By way of example only, a material that has a surface tension of less than about 40 dynes/cm and, preferably less than about 32 dynes/cm and can be used. Hydrophobic polymers, ceramics, cellulosic and metallic materials, or other materials that have been coated to be hydrophobic can be used as well. Suitable materials can include polyethylene, polypropylene, four carbons, silicones, and the like. An exemplary material is Exact Resin No. 4024, manufactured by Exxon.

Inhalation mouthpiece connector130comprises a single hollow tube131that extends outwardly from and is in fluid communication with inhalation chamber120. Inhalation mouthpiece connector130extends along an axis132with respect to axis104. Mouthpiece connector130can be a “universal” mouthpiece connector that allows for connection of various patient connection media, such as, for example, a mouthpiece, a facemask, endotracheal tubes, and other such devices.

In an exemplary embodiment, axis132extends at an angle α generally perpendicularly (about 90°) with respect to axis104, although those skilled in the art will recognize that axis132can extend at an oblique angle relative to axis104. Mouthpiece connector130can be sized for adult use. Alternatively, mouthpiece connector130can be reduced in size for pediatric use.

Inhalation mouthpiece connector130is a generally single hollow tube having a distal first end134connected to inhalation chamber120and a proximal second end136that is adapted to fit into a user's mouth. In an exemplary embodiment, a length of tube131between first end134at inhalation chamber120and second end136is not more than about 2 inches, with a diameter of about ¾ inches. In an exemplary embodiment, mouthpiece connector130is fixedly connected to inhalation chamber120. Alternatively, mouthpiece connector130can be removably connected to inhalation chamber120, such that another mouthpiece or other proximal fitting can be connected to inhalation chamber120. Unlike some prior art inhalation devices, such as, for example, the aerosol inhalation device disclosed in U.S. Pat. No. 5,603,314, inhalation mouthpiece connector130and the path from inhalation chamber120to second end136of tube131notably has an absence of any valves, bends, or other obstructions or tortuous paths therein. The inventors have learned that, in prior art nebulizer devices, such as, for example, the device disclosed in U.S. Pat. No. 5,603,314 to Bono (“Bono”), after a liquid is aerosolized in nebulizer10, the aerosolized liquid must then travel upward, where a rain-off return34is present. Some of the droplets hit rain-off return34and drop off, thereby reducing the volume of aerosolized liquid before even entering aerosol conduit50. Remaining aerosolized liquid enters aerosol conduit50and must pass through a one-way valve51, where remaining larger droplets hit valve51and drop off, thereby further reducing the volume of aerosolized liquid past valve51and reducing the obscuration value of the aerosolized liquid. The remaining aerosolized liquid must continue through aerosol conduit50, making several bends, including a 90 degree bend at fitting60. The bends generate an amount of turbulence that forces some of the aerosolized liquid to hit the walls of aerosol conduit50and fitting60and drop off as well, even further reducing the obscuration value of the aerosolized liquid.

In contrast, with the inventive assembly of the present application, by way of example only, liquid is aerosolized by nebulizer110, which generates the same type of aerosolized liquid as nebulizer10in Bono. It is after nebulizer110where advances provided by the present invention can be realized.

After nebulization by nebulizer110, the aerosolized liquid travels to inhalation chamber120, and then follows a relatively short, straight line path (about 2 inches) along longitudinal axis104without any obstructions or turns whatsoever, to inhalation mouthpiece assembly130, which comprises a single conduit hollow tube131extending along longitudinal axis104, to an inhalation mouthpiece (not shown), where the aerosolized liquid is inhaled by the user. The straight, unobstructed line results in a shorter path between nebulizer110and the user, resulting in higher obscuration values than could be previously achieved.

Therefore, as the inventors believe, the reduction of tortuosity and the absence of obstructions provided by the structure of the device retains the density of aerosolized liquid per volume inside nebulizer device100, specifically at second end136of tube131, resulting in higher obscuration values than were able to be previously achieved, even with the same nebulizer (such as the SWIRLER®”), particularly compared to nebulization devices that provided obstructions such as one-way valves and tortuous paths, such as that disclosed in Bono. Further, the single hollow tube that acts as both an inhalation and an expiration tube distinguishes over Bono, which discloses an inhalation tube and a separate exhalation tube.

In an exemplary embodiment, inhalation mouthpiece connector130has a dead space of less than about 20 cubic centimeters. In an alternative exemplary embodiment, inhalation mouthpiece connector130has a dead space of less than about 10 cubic centimeters. In an alternative exemplary embodiment, inhalation mouthpiece connector130has a dead space of less than about 3.8 cubic centimeters. As used herein, the term, “dead space” is the space within inhalation mouthpiece connector130between first end134at inhalation chamber120and second end136. The dead space is volume within device100in which aerosolized medication is not inhaled into the patient during a breath. Between inhalation and exhalation, nebulizer110still generates aerosolized medication, which travels through inhalation chamber120and into the dead space. But, because the patient is not inhaling at this time the aerosolized medication does not get inhaled. As the patient exhales, the medication is blown out of the dead space back into inhalation chamber120and does not have the opportunity to be inhaled by the patient.

Minimizing the size of the dead space therefore minimizes dilution of the medication in mouthpiece connector130and, consequently, improves the accuracy of dose delivery, maximizes the concentration of the medication dose, and allows a lower amount of the medication to be required to be in nebulizer110in order to deliver a pharmaceutically acceptable amount of the medication to the patient.

First end134generally tapers from a larger to a smaller diameter in the distal to proximal direction. Second end136has a generally oval cross-section to assist a user's mouth in sealing around the exterior of the second end136during use.

While it is desired to use inhalation mouthpiece connector130in order to inhale the aerosolized medication from nebulizer device100, it may not always be practical to use a mouthpiece, such as, for example, for an infant. In such situations, a mask (not shown) can be coupled to the end of inhalation mouthpiece connector130and placed over the user's face. In order to prevent nasal inhalation, which can inadvertently filter some of the medication, a nose clip (not shown) can be clamped over the user's nose, thereby forcing the user to inhale through his/her mouth so that the aerosolized medication is more readily administered to the lungs. Alternatively, with mouthpiece connector130removed from device100, device100can be directly coupled to a tracheotomy tube or a ventilator for direct inhalation into the patient,

A medication injection port140extends outwardly from inhalation chamber120. Injection port140can extend about 180° around inhalation chamber120from inhalation mouthpiece connector130. Those skilled in the art, however, will recognize that injection port140can extend from inhalation chamber120at other locations.

Medication injection port140includes a one-way valve142that extends into inhalation chamber120. One-way valve142allows an aqueous and/or non-aqueous liquid to be injected into inhalation chamber120that prevents the flow of any fluid outwardly from inhalation chamber120.

A connector144, such as, for example, a Luer connector, extends outwardly from injection port140and is in fluid communication with one-way valve142. Connector144is a non-standard connector, such as, for example, a left-hand threaded Luer connection, in order to prevent inadvertent connection of standard syringes with connector144, thereby allowing the introduction of potentially undesired and possibly harmful medications into nebulizer device100. As shownFIG. 1A, connector144can extend coaxially with axis132. Alternatively, connector144can extend below axis132and/or at an angle oblique to axis132.

Optionally, as shown inFIG. 2, aqueous and/or non-aqueous liquid and/or solid medicine201can be relatively sterilely introduced to device100via a pre-loaded syringe200or other medication supply device. Syringe200has a connector202that can only mate with connector144on nebulizer device100. This connector202-to-connector144mating is analogous to a lock and key in which only the appropriate connector144properly connects to connector202. This limitation restricts the ability to use inadvertently syringe200in other devices as well as to prevent other devices from being inadvertently connected to connector144.

In an exemplary embodiment, syringe200contains only a sufficient amount of medication201for a single application. Such a feature allows syringe200to be discarded after medication201is transferred from syringe200to nebulizer device100and also to prevent inadvertent over-medication via syringe200.

Connector144allows for dose individualization, such that standard size doses can be adjusted or diluted to adjust to the patient's response or reaction to or for the medication. Additionally, nebulizer110is refillable without compromising sterility via connector144. By adjusting a standard sized dose, the doses can be individualized for a specific patient's needs. By way of example only, an application of medication via connector144is 5 ml containing 100 mcg (15 mcg/mL) of VIP or avipdatil. The patient's blood pressure can be monitored during the inhalation process. If the medication dose is too large and the blood pressure falls too low, the patient's inhalation of the medication can be briefly stopped, but the treatment can continue because the remaining volume in the nebulizer110can be used to dilute the medication by just adding diluent (i.e., sterilize water, saline, etc.) and thereby reducing the aerosolized concentration from 20 mcg/mL to the desired lower concentration. In an exemplary embodiment, such dilution can be especially useful for short acting drugs, which are those typically lasting less than about 2 to 3 hours. Connector144allows for subsequent connections of syringe200with additional medicine201, allowing device100to be refilled as needed during treatment. By way of example only, nebulizer110can be refilled every several hours, as needed.

The usefulness of dose dilution attribution can be seen also in comparing doses that are useful in children with those that are useful in adults. Adults require higher doses than children. The use of device100in the pediatric population would only require a change in mouthpiece connector130and a diluted dose of medication to achieve a therapeutic effect. No other changes are required in order to treat pediatric patients.

Alternatively, instead of connecting syringe200to connector144, a continuous or intermittent feed device (not shown), such as, for example, an intravenous bag and drip line, particularly for application of short-acting drugs for continuous treatment over the course of several days, can be connected to connector144as long as such continuous feed device has the “lock and key” configuration to mate properly to connector144. Such a device allows the application of larger volumes (i.e., greater than about 9 mL) than can be stored within nebulizer110, as well as for longer durations of treatment (i.e., greater than one half hour).

Short acting drugs like VIP and related peptides, aviptadil, phentolamine or sildenafil are ideal for device100because such medications require continuous flow or longer than one puffing or inhalation session and such drugs are so active that the volume of each drug needs to be individualized for the particular patient. Again, this would apply to drugs with short half-lives and a short duration of action such as VIP and sildenafil. The inventors note that Aviptadil is not presently approved for oral inhalation by the U.S. Food and Drug Administration (“FDA”). The present device and method of using the device with Aviptadil are contemplated only after FDA approval.

Still alternatively, instead of using connector144to inject the medication into device100, connector144can be eliminated and device100can be pre-filled with a therapeutically sufficient amount of the medication. In essence, pre-filling device100with the medication makes device100a single use device. This feature has the benefit of ensuring delivery of the medication into device100without inadvertent contamination of the medication via the external environment.

Optionally, first and second finger grips150,152can be formed in or located on inhalation chamber120. The first finger grip150can be located vertically above medication injection port140, while second finger grip152can be located vertically below medication injection port140. Finger grips150,152are contoured to provide a comfortable mechanism for the user to grasp and hold nebulizer device100during use.

Referring back toFIG. 1A, a filter assembly160is located vertically above and is in fluid communication with inhalation chamber120and extends along longitudinal axis104. Filter assembly160includes a filter medium162and a heat and moisture exchange (“HME”) filter164that are used to trap and return non-inhaled aerosol particles of medication to nebulizer110for re-nebulization and inhalation.

In an exemplary embodiment, filter medium162can be a product manufactured by 3M under the trademark FILTRETE, although those skilled in the art will recognize that other filter media can be used. Further, as shownFIG. 1B, filter medium162and HME filter164can both be removed from filter assembly160and replaced with a replacement filter medium162and/or HME filter164.

Optionally, filter medium162is electrostatically charged to enhance the recovery of non-inhaled medication. Filter medium162can be electrostatically charged to a charge density within the range of between about 10 and about 125 nano-Coulombs per square centimeter (“nC/cm2”), or at least about 50 nC/cm2and preferably about 75 nC/cm2. Filter medium162can be a hydrophobic material.

An exit port170is in direct fluid communication with filter assembly160and extends along longitudinal axis104. Exit port170allows exhaled air from the user to exit nebulizer device100. Additionally, exit port170allows inhaled air to pass through exit port170and filter assembly160into inhalation chamber120for inhalation by the user. Exit port170is sized to allow connection of a respiratory resuscitation bag or, alternatively, an external ventilator connection.

The vertical nature of device100is deliberate and by design because testing of the relationship between droplet size and obscuration can be altered by airflow path. Those skilled in the art may recognize this notion to be understood that the nature or the degree of droplet size homogeneity and obscuration may depend, in addition to the straight line, non-obscured path from inhalation chamber120to second end136of tube131, but also on a non-angled path to the exit ports. If exit port170is angled with respect to longitudinal axis104, then the “pairing” of low droplet size and obscuration value, as discussed above, may change.

As shown inFIG. 1B, exit port170can be releasably coupled to inhalation chamber120, such that exit port170can be removed from inhalation chamber120for access to filter assembly160. Exit port170can be releasably coupled to inhalation chamber120, such as, for example, by a threaded connection.

In use, nebulizer device100is held such that gas inlet102is at the bottom of nebulizer device100and exit port170is at the top of nebulizer device100. Connector202on syringe200is connected to connector144on injection port140and medication in syringe200is injected through injection port140, and into inhalation chamber120, where the medication falls via gravity into nebulizer device100.

A pressurized gas supply is connected to the pressurized gas inlet102at the bottom of nebulizer device100. In an exemplary embodiment, the pressurized gas supply can be air. Alternatively, the pressurized gas supply can be another gas, such as, for example, oxygen, or other biocompatible gas.

The pressurized gas enters nebulizer110and mixes with the medication, generating an aerosol of medication. The user places his/her lips around the proximal end136of mouthpiece connector130and inhales, drawing atmospheric air through exit port170and filter assembly160, into inhalation chamber120and through mouthpiece connector130and into the user's lungs. As the inhaled air passes through inhalation chamber120, the aerosolized medication in inhalation chamber120is inhaled as well.

The user exhales through mouthpiece connector130and the exhaled air passes through inhalation chamber and filter assembly160and exits through exit port170. Any medication in that flow path is caught by filter assembly160, so that the medication does not exit through exit port170. The electrostatic charge of filter assembly160encourages agglomeration of the medication, forming particles large enough to drop via gravity from filter assembly160, through inhalation chamber120, and into nebulizer110, where the medication is re-nebulized for inhalation.

The nebulization and inhalation of the medication are repeated until the medication is generally used up or after a predetermined period of time when it is determined that a sufficient amount of the medication has likely been inhaled by the user. The pressurized gas supply is secured before removing the pressurized gas supply from pressurized gas inlet102.

The present invention, due to its efficiency, provides the ability for a high and therapeutically meaningful amount of the stated dose to reach deep lung bronchioles and the alveolar surfaces in rapid fashion. It is possible to achieve a reduction in the amount of medication required in nebulizer device100in order to provoke a therapeutically effective dose-response of the medication. For example, for the drug tobramycin, the present therapeutically effective dose of 300 mg per 5 mL in a prior art device can be dosed at 300 mg per 5 mL or alternatively reduced to less than less than 300 mg per 5 mL, alternatively less than 250 mg per 5 mL, and alternatively less than 200 mg per 5 mL, and still alternatively less than 150 mg per 5 mL using nebulizer device100. Tobramycin can also be provided by continuous uninterrupted therapy, as in a slow continuous infusion (vs. intermittent use). Tobramycin can therefore be administered via device100and a continuous rate of between about 40 mg per hour and about 50 mg per hour.

Other drugs can also be provided by continuous therapy. Continuous therapy can be very important for short acting drugs like VIP cogeners, VIP itself, Aviptadil, Sildenafil, Iloprost, or other short-acting medications.

For the drug aztreonam, a short-acting antibiotic, the present therapeutically effective dose of 75 mg per 1 mL in a prior art device can be dosed at 75 mg per 1 mL or alternatively reduced to less than 75 mg per 1 mL, alternatively, less than 50 mg per 1 mL, and alternatively, to less than 40 mg per 1 mL using nebulizer device100.

For the drug colistin, the present therapeutically effective dose of at least one million units can be dosed at 1 million units or alternatively reduced to less than 1 million units, alternatively, to less than 750,000 units, and still alternatively, to less than 500,000 units using nebulizer device100.

For the drug albuterol, the present therapeutically effective dose of 1.25 mg per 3 mL can be dosed at 1.25 mg per 3 ml or alternatively reduced to less than 1.25 mg per 3 mL, alternatively, less than 1 mg per 3 mL and alternatively, to less than 0.75 mg per 3 m.

For the drug alpha-1 proteinase inhibitor (API), the present therapeutically effective dose of at least 100 mg can be dosed at 100 mg or alternatively reduced to less than 100 mg, alternatively, to less than 75 mg, and still alternatively, to less than 50 mg using nebulizer device100.

For the drug iloprost, the present therapeutically effective dose of 5 mcg can be dosed at 5 mcg or alternatively reduced to less than 5 mcg, alternatively, less than 4 mcg and alternatively, less than 3 mcg using nebulizer device100.

For the drug sildenafil, the present therapeutically effective dose of at least 10 mg can be dosed at 10 mg or alternatively reduced to less than 10 mg, alternatively, less than 7.5 mg and alternatively, less than 5 mg using nebulizer device100.

For the drug vasoactive intestinal peptide (VIP) or like congeners or peptides, the present therapeutically effective dose of at least 1 mcg can be dosed at 1 mcg or alternatively can be reduced to less than 1 mcg, alternatively, less than 0.75 mcg and alternatively, less than 0.5 mcg using nebulizer device100.

For the drug insulin, the present therapeutically effective dose of 1 IU per kilogram body weight can be dosed at 1 IU per kilogram body weight or alternatively reduced to less than 1 IU per kilogram body weight, alternatively, less than 0.75 IU per kilogram body weight and alternatively, less than 0.50 IU per kilogram body weight using nebulizer device100.

The drug examples as illustrated above are for their primary indications. Those skilled in the practice of medicine or in the treatment of the sick, or those trained in pharmacy, know that a drug can have more than one action and because of this attribute, a drug described above be used to treat more than one infectious condition, or varied types of pulmonary or systemic disease requiring different doses than those stated in examples presented above.

The duration of use of nebulizer device100in order for a patient to inhale a therapeutically effective dose of medication can be affected by both the flow rate of pressurized gas transmitted to nebulizer device100via pressurized gas inlet102, as well as by the pressure of that gas. In an exemplary embodiment, for a 5 mL dose, the pressurized gas can be at 50 PSI and flowing at a rate of between about 8 and about 12 liters per minute and, in a further exemplary embodiment, about 10 liters per minute. Other exemplary depletion times of the medication are a factor of flow rate, and pressure are shown in the chart below.

Flow RateDepletion time in minutes8 L per minute4.005.075.289 L per minute3.504.694.8310 L per minute3.163.334.1611 L per minute2.593.023.4012 L per minute2.382.903.23Pressure50 PSI45 PSI40 PSI

Where there are concerns about overpressure of the patient lungs, it is noted that the pressures cited above are only required to generate the aerosol and not to pressurize the lungs.

Experimental testing, such as, at the above-listed flow rates and pressures, generated trace residual amounts of fluid within nebulizer110due to the extreme efficiency of nebulizer110. Trace residual amounts of the following fluids, which may be representative of medicines to be nebulized within nebulizer device100work: Mazola oil (example of an oil-based liquid, such as a surfactant)—0.002 pounds; 0.65% sodium chloride—0.001 pounds; H2O—0.001 pounds; and non-fat milk (example of micro-emulsion or micro-colloidal system)—0.002 pounds. It is believed that, for a 5 mL aqueous and/or non-aqueous liquid dose within nebulizer110, over 99% of the aqueous and/or non-aqueous liquid is nebulized over a time frame of less than about 6 minutes. Because of the low residual amounts of the medication retained in device100after administering the medication to the patient, a more accurate dosage of the medication is provided to the patient, requiring less medication to be initially provided in nebulizer110. Also, pre-packaging the medication within nebulizer110or injecting the medication into device100from syringe200reduces the likelihood of contaminating the medication from the exterior environment.