WO2014113638A1

WO2014113638A1 - Multi-use albuterol maintenance therapy formulations and devices therefor

Info

Publication number: WO2014113638A1
Application number: PCT/US2014/011991
Authority: WO
Inventors: Joseph Milligan; Jason SHAEFFER; David N. PHAM
Original assignee: Aer Devices, Inc.
Priority date: 2013-01-17
Filing date: 2014-01-17
Publication date: 2014-07-24

Abstract

Contemplated devices, formulations, and methods allow for significant reduction of albuterol using an on-demand thermal vaporizer while maintaining bioequivalent functional response to currently known modes of administration. In particularly preferred aspects, the total administered dose is less than 4% of an administered dose of an aqueous solution given via a known nebulizer, and less than 15% of an administered dose of an aqueous/ethanolic solution given via a known metered dose inhaler.

Description

MULTI-USE ALBUTEROL MAINTENANCE THERAPY FORMULATIONS AND

DEVICES THEREFOR

[0001] This application claims the benefit of US Provisional Application Serial Number 61/753743, which was filed January 17, 2013, and which is incorporated by reference herein.

Field of The Invention

[0002] The field of the invention is devices and methods for pulmonary delivery of drugs, and especially devices and methods for multi-use pulmonary delivery of bronchodilatory drugs for maintenance treatment of a patient.

Background of the Invention

[0003] Chronic obstructive pulmonary disease (COPD) is a fairly common pulmonary disease in which air flow to and from the lungs is compromised. Likewise, allergen- and exercise-induced asthma are fairly common disorders that are generally characterized by airflow obstruction and bronchospasm. Among other options for treatment of COPD and asthma, albuterol (salbutamol, (RS)-4-[2-(tert-butylamino)-l-hydroxyethyl]-2-(hydroxymeth- yl)phenol) is fairly effective in treatment of symptoms associated with COPD and asthma.

[0004] For example, COPD patients are often on a maintenance treatment with inhaled albuterol in which a mechanical (e.g., ultrasonic or impact) nebulizer generates a mist that carries the albuterol to the lungs. While such nebulizer maintenance treatment is conceptually very simple, patients will typically be restricted to home treatment as the nebulizer is relatively bulky and often dependent on line voltage. Alternatively, albuterol can also be administered as a highly concentrated spray from a hand-held metered dose inhaler (MDI). However, use of an MDI for delivery is typically limited to use as a rescue inhaler due to the high drug concentration and so not suitable for maintenance therapy.

[0005] In addition, and particularly where an ultrasonic or impact nebulizer is used, the albuterol containing liquid that is placed into the vaporization chamber must be completely used or the remaining liquid must be discarded. Moreover, due to the constant concentration of albuterol in the mist from a nebulizer, the patient can typically not modify the amount of albuterol taken per inhalation. Similarly, MDI delivery is limited to a constant dose of albuterol taken per inhalation. Moreover, and regardless of the mode of administration (i.e., nebulizer or MDI), pediatric use is often difficult as children tend to have difficulty with the operation of a nebulizer mask or MDI. In addition, the recently revised guidelines for asthma treatment by the National Institutes of Health recommended that pediatric patients use the lowest beta-agonist doses needed to control symptoms. However, lowest beta-agonist doses are typically achieved by dilution of the treatment solution, which is potentially dangerous due to calculation errors and/or contamination of residual medication.

[0006] Regardless of the above difficulties, side effects of albuterol are fairly common and include tachycardia, uncontrollable shaking of a part of the body, nervousness, headache, nausea, vomiting, cough, throat irritation, muscle, bone, or back pain, and in severe cases chest pain, difficulties breathing, difficulty swallowing, and swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs, all of which tend to increase in frequency and/or severity with increasing administered dosage. Therefore, it would be highly desirable to have compositions and methods that would allow administration of a reduced dosage of albuterol (and other beta receptor agonists) while having bioequivalent functional response/therapeutic effect as it is thought that such reduced dosages will significantly reduce side effects. Viewed from a different angle, it would be also highly advantageous to have compositions and methods that increase potency of albuterol and other beta receptor agonists when administered via pulmonary route.

[0007] Thus, even though various uses, devices, and methods for pulmonary administration of albuterol and other beta2 -receptor agonist bronchodilators are known, there is still a need to provide improved compositions, methods and devices, especially where administration is for maintenance therapy.

Summary of The Invention

[0008] The present invention is directed to various compositions, methods, uses, devices and formulations for pulmonary administration of a therapeutically effective amount of a drug, and especially a beta2 -receptor agonist bronchodilator and/or corticosteroid to a patient in need thereof. Among other advantages, the compositions, methods, and uses according to the inventive subject matter unexpectedly allow for substantial reduction of total administered dose of the drug using an on-demand thermal vaporizer while maintaining a bioequivalent functional response to currently known modes of administration. Viewed from a different perspective, using inventive compositions and methods significantly increases potency of the beta2 -receptor agonist bronchodilator and/or corticosteroid, and thus allows for a substantial reduction in the required administered dose, which in turn will reduce the incidence and/or severity of side effects associated with the drugs.

[0009] In one aspect of the inventive subject matter, the inventors contemplate compositions, methods, and use of a low-molecular weight polyol as thermo-nebulizable carrier for a beta2- receptor agonist bronchodilator (and/or corticosteroid) to reduce the administered dosage of the beta2 -receptor agonist bronchodilator formulation while maintaining a desired functional response for the beta2 -receptor agonist bronchodilator.

[0010] In particularly preferred compositions, methods, and uses, the thermo-nebulizable carrier is or comprises a low-molecular weight polyol, most preferably in an amount of between 80-92 vol% of the formulation. For example, suitable thermo-nebulizable carrier are or comprise propylene glycol, glycerol, and/or PEG400 (polyethylene glycol) in a total amount of between 80-92 vol% of the formulation. Where the beta2 -receptor agonist bronchodilator is a short-acting agonist, especially contemplated agonists include albuterol, albuterol sulfate, levalbuterol, terbutaline, pirbuterol, procaterol, clenbuterol, metaproterenol, fenoterol, bitolterol mesylate, ritodrine, and isoprenaline, and where the beta2 -receptor agonist bronchodilator is a long-acting agonist, preferred agonists include salmeterol, formoterol, bambuterol, clenbuterol, olodaterol, and indacaterol. Especially preferred beta2- receptor agonist bronchodilator include albuterol, and albuterol sulfate or other short-acting antimuscarinic agonist such as ipratropium bromide.

[0011] While not limiting to the inventive subject matter, it is contemplated that the beta2- receptor agonist bronchodilator is present in the formulation at a concentration of between 0.25 mg/ml and 5.0 mg/ml, and in some aspects, the low-molecular weight polyol is propylene glycol and the beta2 -receptor agonist bronchodilator is albuterol. In other aspects, propylene glycol is present in an amount of between 80-92 vol% of the formulation and albuterol is present in the formulation at a concentration of between 0.25 mg/ml and 5.0 mg/ml.

[0012] Therefore, and viewed from another perspective, the inventors also contemplate compositions, methods, and use of a thermal nebulizer to reduce the administered dosage of a beta2 -receptor agonist bronchodilator (and/or corticosteroid) while maintaining the functional response for the beta2 -receptor agonist bronchodilator, wherein the thermal nebulizer uses a low-molecular weight polyol in a formulation as thermo-nebulizable carrier for a beta2- receptor agonist bronchodilator.

[0013] For example, in some aspects, the administered dosage can be reduced from 2500 meg per administration cycle via a mechanic nebulizer (e.g., piston nebulizer, or ultrasonic nebulizer) to less than 100 meg per administration cycle via a thermal nebulizer. In other aspects, the administered dosage can be reduced from 540 meg per administration cycle via a metered dose inhaler to less than 100 meg per administration cycle via a thermal nebulizer. Most typically, but not necessarily, the functional response is an improvement of at least 15% in FEV1 (forced expiratory volume at 1^st second).

[0014] In especially contemplated aspects, the thermal nebulizer is a hand-held on-demand thermal nebulizer, and the beta2 -receptor agonist bronchodilator is a short-acting agonist (e.g., albuterol). As discussed above, suitable low-molecular weight polyols include propylene glycol, glycerol, and PEG400 (polyethylene glycol), which are typically present in a total amount of between 80-92 vol% of the formulation. It is further contemplated that the dosage of the beta2 -receptor agonist bronchodilator administered via the thermal nebulizer is between 50-100 meg. Therefore, one exemplary use will employ propylene glycol as the low- molecular weight polyol, albuterol as beta2 -receptor agonist bronchodilator, and produce a functional response of an at least 15% improvement in FEV1 after administration of between 50-100 meg of the bronchodilator.

[0015] In yet another aspect of the inventive subject matter, the inventors contemplate a liquid formulation that includes a low-molecular weight polyol in an amount of between 80- 92 vol% and a beta2 -receptor agonist bronchodilator (and/or corticosteroid) at a

concentration of between 0.25 mg/ml and 5.0 mg/ml. Most typically, the low-molecular weight polyol is propylene glycol, glycerol, and/or PEG400, and the beta2 -receptor agonist bronchodilator is a short-acting agonist (e.g., albuterol, albuterol sulfate, levalbuterol, terbutaline, pirbuterol, procaterol, clenbuterol, metaproterenol, fenoterol, bitolterol mesylate, ritodrine, ipratropium bromide, or isoprenaline), and/or a long-acting agonist (e.g. salmeterol, formoterol, bambuterol, clenbuterol, olodaterol, or indacaterol). Where desirable, the liquid formulation may further include a surfactant and/or a co-solvent, for example, to improve uniformity of the vapor droplets and/or bioavailability. Most preferably, the low-molecular weight polyol is present in an amount of between 84 ⁺/_ 2 vol%, and/or the beta2 -receptor agonist bronchodilator is present at a concentration of 0.85 /_ 0.2 mg/ml. [0016] Consequently, the inventors also contemplate a kit that comprises a liquid formulation in a container, wherein the liquid formulation comprises a beta2 -receptor agonist

bronchodilator (and/or corticosteroid) in a thermo-nebulizable carrier, wherein the container is sized and dimensioned for use in an on-demand thermal nebulizer (e.g., allows complete insertion into a hand-held on-demand thermal nebulizer), and wherein the liquid formulation is present in the container in a volume suitable for at least ten nebulization cycles (e.g., has a volume of between 1-5 ml). For example, suitable containers may be configured as cartomizer container, a clearomizer container, or an atomizer container.

[0017] In particularly contemplated kits, the thermo-nebulizable carrier comprises propylene glycol, glycerol, and/or PEG400, typically in a total amount of between 80-92 vol% of the formulation. Additionally, it is generally preferred that the beta2 -receptor agonist

bronchodilator is a short-acting agonist (e.g., albuterol).

[0018] Therefore, the inventors also contemplate a highly effective hand-held thermal nebulizer for intermittent and on-demand thermo-nebulization of a pharmaceutical formulation, especially for treatment of chronic obstructive pulmonary disease and/or asthma that delivers a relevant drug (e.g., beta2 -receptor agonist bronchodilator or corticosteroid) to the patient. Particularly preferred thermal vaporizers comprise a heating filament that is fluidly coupled (e.g., via a wicking material and/or structure or via a drop pathway) to a reservoir suitable to contain the pharmaceutical formulation for thermo-nebulization. An electronic circuit is then configured to record individual and/or cumulative on-demand thermo-nebulization, and an output modality is configured to provide an indication of the individual and/or cumulative on-demand thermo-nebulization. Most typically, the hand-held thermal nebulizer is configured as a pen sized thermal nebulizer, and the reservoir has a volume suitable to contain the pharmaceutical formulation in an amount sufficient for at least three distinct administration cycles. Particularly preferred output modalities comprise a display and/or a data port that is configured for electronic transfer of the indication (e.g., to a personal computer, Internet, cellular network, etc.). In still further preferred aspects, the pharmaceutical formulation comprises a low-molecular weight polyol (e.g., propylene glycol and/or glycerol) and a beta2 -receptor agonist bronchodilator (e.g., albuterol and/or corticosteroid).

[0019] In still further contemplated aspects of the inventive subject matter, the inventors also contemplate a method of increasing potency of a drug in a drug formulation, wherein the drug is a beta2 -receptor agonist bronchodilator, and wherein the potency is with respect to a functional response of a patient to the drug. Such methods will particularly include a step of combining the beta2 -receptor agonist bronchodilator with a thermo-nebulizable carrier to so form a thermo-nebulizable solution that is then administerable and/or administered to a patient. In especially contemplated aspects, the increased potency requires administration of less than 20% of the administered dose for the same functional response as compared to administration of the drug when administered via metered dose inhaler, or the increased potency requires administration of less than 4% of the administered dose for the same functional response as compared to administration of the drug when administered via a mechanical vaporizer.

[0020] As noted above, the thermo-nebulizable solution may comprise a low-molecular weight polyol (e.g., propylene glycol, glycerol, and PEG400) in an amount of between 80-92 vol% of the formulation, and/or the beta2 -receptor agonist bronchodilator is a short-acting agonist (e.g., albuterol, albuterol sulfate, levalbuterol, terbutaline, pirbuterol, procaterol, clenbuterol, metaproterenol, fenoterol, bitolterol mesylate, ritodrine, ipratropium bromide, or isoprenaline) at therapeutically effective concentrations (e.g., albuterol at a concentration of between 0.25 mg/ml and 5.0 mg/ml).

[0021] Therefore, the inventors also contemplate a method of reducing the total administered quantity of a drug to a patient while maintaining a predetermined functional response in the patient, wherein the drug is a beta2 -receptor agonist bronchodilator (and/or corticosteroid), and wherein the reduced total administered quantity of the drug is relative to that of the drug when administered via a mechanic (piston or ultrasonic) nebulizer at a dosage for the same functional response. Especially preferred methods will include a step of administering a reduced total administered quantity of the beta2 -receptor agonist bronchodilator using a thermo-nebulizer from a thermo-nebulizable solution. For example, the reduced quantity is less than 20% of the quantity of the drug for the same functional response as compared to administration of the drug when administered via metered dose inhaler, and the reduced quantity is less than 4% of the quantity of the drug for the same functional response as compared to administration of the drug when administered via a mechanical vaporizer. Most preferably, the thermo-nebulizable solution comprises a low-molecular weight polyol (e.g., propylene glycol, glycerol, and PEG400) in an amount of between 80-92 vol%> of the formulation, and/or the beta2 -receptor agonist bronchodilator is a short-acting agonist (e.g., albuterol, albuterol sulfate, levalbuterol, terbutaline, pirbuterol, procaterol, clenbuterol, metaproterenol, fenoterol, bitolterol mesylate, ritodrine, ipratropium bromide, or

isoprenaline) at a therapeutically effective concentration (e.g., albuterol is present in the formulation at a concentration of between 0.25 mg/ml and 5.0 mg/ml).

[0022] Likewise, the inventors also contemplate a method of reducing a side effect of a beta2 -receptor agonist bronchodilator (and/or corticosteroid) in a patient while maintaining a predetermined functional response in the patient, wherein the reduced side effect of the drug is relative to that of the drug when administered via a mechanic (e.g., piston or ultrasonic) nebulizer at a dosage for the same functional response. In especially contemplated methods, the beta2 -receptor agonist bronchodilator is administered using a thermo-nebulizer (and especially hand-held on-demand thermo-nebulizer) from a thermo-nebulizable formulation in a quantity to achieve the predetermined functional response (e.g., improvement of at least 15% in FEV1) in the patient. Among other side effects that can be reduced, especially contemplated side effects include tremor, anxiety, headache, muscle cramps, dry mouth, palpitation, and/or tachycardia. In further particularly preferred methods, the administered dosage by the thermo-nebulizer is less than 100 meg per administration cycle, which is most typically performed without loss of the nebulized formulation.

[0023] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments, along with the accompanying drawing figures in which like numerals represent like components.

Brief Description of The Drawing

[0024] Figure 1 is table listing exemplary treatment results of various patients using devices, compositions, and methods according to the inventive subject matter compared to two known treatment regimens.

[0025] Figures 2A-2F are graphs illustrating the data of the table of Figure 1.

[0026] Figure 3 is an exemplary graph showing improvement in FEV1 in patients treated with compositions and methods according to the inventive subject matter and comparative data. [0027] Figure 4 is an exemplary graph contrasting various treatment options and outcome as determined by improvement of FEV1.

Detailed Description

[0028] The inventors have now discovered that various drugs for pulmonary administration can be delivered to the lungs of a patient via thermal nebulization of a drug solution that contains a thermo-nebulizable carrier. In especially preferred aspects, the thermo-nebulizable carrier comprises or is a low-molecular weight polyol, and administration is in an intermittent and on-demand manner that is typically loss-free. Administration according to the inventive subject matter advantageously overcomes numerous difficulties associated with heretofore known devices and compositions, including relatively low potency, lack of accurate control of administered dose, loss of active ingredient due to continuous nebulization, and lack of portability of the nebulizer.

[0029] Table 1 below provides exemplary and typical dosage regimens for the various forms of administration for albuterol sulfate that have been reported to achieve a >15% increase in FEV1 (forced expiratory volume, first second), and contrasts these with the dosage regimen of the inventive subject matter. The nebulizer of Table 1 is a mechanical nebulizer using an aqueous solution of albuterol, the MDI of Table 1 is a metered dose inhaler using albuterol in 134a as propellant with minor quantities of ethanol. In this context, it should be noted that the previously available albuterol MDI formulations used chlorofluorocarbons as the propellant, and small quantities (<5vol%) of propylene glycol were used as a surfactant, which is replaced in currently available formulations by ethanol in albuterol MDI formulations that have HFA (1,1,1,2-tetrafluoroethane, also known as 134a) as the propellant as, for example, described in US 6,416,743. Not listed here is albuterol delivery via dry powder inhaler (e.g., Rotahaler, Diskhaler), which was deemed bioequivalent to an MDI (see Hindle et al., Chest 1995 Mar;107(3):629-33). ODTN is on-demand thermal nebulizer with 84 ⁺/_ 2 vol% propylene glycol.

Route/Device Total Administered Quantity

Oral/Tablet 2,000 meg per tablet

Pulmonary/Nebulizer 2,500 meg per ampoule

Pulmonary/MDI 540 meg total over 6 inhalations

(90 meg per puff) Pulmonary/ODTN 67 meg total over 15 inhalations

(4.46 meg per puff)

[0030] It is generally contemplated that suitable devices are thermal nebulizers, and it is typically preferred that the thermal nebulizer is configured as a hand-held nebulizer pen. For example, numerous currently commercially available thermal nebulizers (also known as electronic vaping device or electronic cigarettes) are appropriate for use in conjunction with the teachings presented herein, which may be further modified as also further discussed in more detail below. Thus, all or almost all known hand-held thermal nebulizers are deemed suitable for use herein, and exemplary nebulizers are disclosed in WO 201 1/146375 A2 , WO 201 1/146330A2 , US 2012/0138054A1 , US 2012/01 18301A1 , US 201 1/0278189A1 , US 8,127,772B2 , and GB 2,476,612B, all of which are incorporated by reference herein.

[0031] It should be particularly noted that such devices nebulize the drug-containing liquid only on demand (e.g., upon actuation by inhalation, typically triggered by air flow and/or reduced pressure, upon a user activating the device, etc.), and that the quantity of nebulized liquid is directly and effectively controllable and/or recordable, which advantageously allows to electronically record, transmit, and/or display the administered dose, usage patterns, total used drug, etc. For example, using a memory storage element, daily and weekly use patterns can be recorded and directly transmitted to a physician or other health care professional via known communication channels (e.g., cellular network, Internet, USB port, etc.).

Alternatively, or additionally, delivered quantities of drug can also be displayed in real-time to allow a user, parent/guardian to ascertain that a minimum recommended dosage has indeed been delivered to the patient. In still further preferred embodiments, a safety circuitry may be included into the device to disable vaporization to so help prevent inadvertent overdosing of an inhaled drug. Therefore, it should be appreciated that devices according to the inventive subject matter will preferably include an output modality configured to provide an indication of the individual and/or cumulative on-demand thermo-nebulization (e.g., via a display and/or a data port configured for electronic transfer of the indication), as well as control circuitry that allow activation or deactivation as a function of a previously authorized or prescribed use pattern.

[0032] As most of the inhaled drugs have at least some thermal sensitivity, it is preferred that the vaporization coil is configured and operated by electronic control circuitry to avoid adverse effects of the coil on the drug. For example, multiple shorter coils could substitute longer single or fewer coils. Thus, it should be appreciated that the residence time of the drug at or near the heating filament is sufficiently short to minimize thermal degradation of the drug, particularly where a co-solvent or co-solvent system is used that allows vapor formation at a temperature below 100°C (e.g., between 40-80 °C). Likewise, the coils are preferably thermally controlled such as not to exceed a safe maximum temperature and/or coils could be alternately heated to reduce overall exposure of the drug solution to the heated coils. In most preferred aspects, the coils will be configured and/or operated such that at least 80%, more typically at least 90%, even more typically at least 95%, and most typically at least 98% of the drug passing from liquid to vaporized state remain chemically unchanged. Consequently, stringent thermal control via the electronic circuitry in the nebulizer with parameters matched to the thermal sensitivity of the drug is expressly contemplated. Consequently, the electronic circuitry may be designed or programmable to the specific optimum nebulization profile for a particular drug to so reduce or entirely avoid thermal degradation of the drug and/or achieve a desirable average particle size. Where the drug is sensitive to oxygen and/or elevated temperatures, it is preferred that the vaporizing device will include a seal that prevents the solution from exposure to open air. In some cases, oxygen scavenging cartridges may be provided upstream of an opening that compensates for vacuum pressure in the liquid reservoir.

[0033] Moreover, the inventor have also noted that the particle size distribution of aerosols produced by thermal nebulizers (as measured in an undiluted state by a spectral transmission procedure and after high dilution with an electrical mobility analyzer) is generally very small and in the range of 10-400 nm range (depending on measurement; light scattering vs. electric mobility) and monomodal (i.e., having only one peak in a size distribution profile).

Moreover, a typical particle number concentration using thermal nebulizers with a thermo- nebulizable formulation is in the 10⁹-10¹⁰ particles/cm³ range. While not limiting to the inventive subject matter, the inventors contemplate that use of a thermal nebulizer together with the thermo-nebulizable formulations contemplated herein will produce an average particle size diameter of the particles that is substantially smaller than that achieved by an MDI (typically 0.5-5 micrometer range), which may further assist in deep penetration of the nebulized formulation to the lung. Thus, it is contemplated that the vaporization coils are configured such that the vapor droplet size is in a range of between about 1 nm and 3 micron, more typically between about 5 nm and 300 nm, and most typically between about 5 nm and 200 nm. Likewise, it should be appreciated that a more uniform droplet size is generally advisable, and it is typically preferred that the coil is heated and the formulation is formulated such that at least 50%, more typically at least 70%, and most typically at least 85% of all droplets fall within the range of 20-80 percentile. In addition, contemplated nebulizers will be configured such that between 5 and 15 microliters of nebulized formulation per inhalation is provided to a user.

[0034] Most typically, contemplated vaporizers will have a reservoir that holds at least 1.0ml, more typically at least 2.0ml, and most typically at least 3.0 ml of albuterol or other drug solution. Consequently, contemplated devices will allow a large number of administration cycles, and most typically allow for at least five administration cycles (i.e., multiple inhalations to deliver drug in an amount to achieve desired therapeutic effect, e.g., increase in FEV1 of at least 15%), more typically at least ten administration cycles, and most typically at least 20 administration cycles. Moreover, it should be noted that vaporizers contemplated herein may have more than one fluidly separated reservoir to hold two or more different drugs or two or more different potencies of the same drug (e.g., one for maintenance therapy and one for rescue use). Of course, it should also be noted that contemplated devices will include a suitable power source (typically but not necessarily rechargeable), and especially preferred power sources include Li-ion and Li-polymer batteries.

[0035] Depending on the type of device and drug used, it should be noted that the reservoir may be configured accordingly, and it is generally contemplated that the reservoir may be configured as cartomizer or clearomizer (where the fluid chamber and the heating element in single unit with fluid transfer via polyfill or silica wicking to heating coil). However, in other aspects, it is also contemplated that the reservoir may be configured as an atomizer (where the fluid chamber and the heating element as separate units with fluid transfer via drip to heating coil).

[0036] With respect to suitable drugs for pulmonary administration it should be appreciated that all drugs are deemed appropriate that allow for such route of administration. However, especially preferred drugs include various bronchodilators, vasodilators (e.g., nitroglycerin), metabolic modulators (e.g., insulin), steroids (e.g., corticosteroids), etc. For example, where bronchodilators are employed, it should be recognized that numerous beta2 -receptor agonist bronchodilator are especially preferred. For example, suitable short-acting beta2 -receptor agonist bronchodilators include albuterol, albuterol sulfate, levalbuterol, terbutaline, pirbuterol, procaterol, clenbuterol, metaproterenol, fenoterol, bitolterol mesylate, ritodrine, ipratropium bromide, and/or isoprenaline, while suitable long-acting agonists include almeterol, formoterol, bambuterol, clenbuterol, olodaterol and/or indacaterol, and all reasonable combinations thereof. Still further, it should be noted that additional

pharmaceutical agents may be co-administered (contemporaneously with the same device or sequentially with the same or different device), and preferred agents include steroids

(particularly corticosteroids), and various long-term control medications, and especially cromolyn sodium, nedocromil, various immunomodulators, leukotriene modifiers, and/or methylxanthins, and various antibiotics such as ciprofloxacin, tobramycin or aztreonam.

[0037] Suitable dosages for contemplated drugs will generally be in the range of O.Olx to lOx, and more typically 0.05-0.5x (or 0.5-1.5x, and in some cases 1.5-5x) of the dosage ordinarily administered via pulmonary route. As appropriate dosages and dosage ranges are already known for the respective drugs and conditions, the skilled artisan will be readily appraised of suitable concentrations for use with devices presented herein. Viewed from a different perspective, contemplated pharmaceutical agents will be present in the thermo- nebulizable formulation in a quantity such that a desired therapeutic effect will be achieved by between 1 and 50 individual inhalations, more typically between 3 and 30 individual inhalations, and most typically between 5 and 20 individual inhalations (providing between 5 and 15 microliters of nebulized formulation per inhalation). For example, where the drug is a beta2 -receptor agonist bronchodilator, the drug may be present at a concentration of 0.1-0.5 mg/ml, 0.5-1.5 mg/ml, 1.5-5 mg/ml, or 5-50 mg/ml. In especially preferred aspects, where the beta2 -receptor agonist bronchodilator is albuterol, the beta2 -receptor agonist bronchodilator is present at a concentration of 0.85 /_ 0.2 mg/ml.

[0038] In still further contemplated aspect of the inventive subject matter, the drug or drugs are preferably formulated in a solution suitable for thermo-nebulization. Thus, contemplated formulations will typically comprise a water miscible polyol compound, and particularly a glycol or glycerol as further discussed in more detail below. The drug is preferably entirely soluble at the use concentration in both the water and the polyol phase. Alternatively, the polyol may be a co-solvent that increases solubility of the drug. However, solubility is not a necessary prerequisite and it should therefore also be recognized that the drug may be present in form of an emulsion or in microcrystalline suspension in the thermo-nebulizable formulation. [0039] Additionally, and where desired, additional co-solvents may be employed all of which are preferably completely miscible in the quantities present in the solution. For example, suitable co-solvents will include various alcohols, ethers, esters, oils, fatty acids, N-methyl- pyrrolidone, etc. Such co-solvents may improve solubility of the drug in the water polyol mixture, but may also be useful in improving stability of the drug, typically against oxidation (which may be due to storage and/or heat exposure). Therefore, it is also contemplated that the formulation may comprise one or more anti-oxidants, or sacrificial compounds that preferentially oxidize. For example, albuterol is often subject to oxidation and forms albuterol-aldehyde. In preferred aspects of the inventive subject matter, the solvent, co- solvent, and optional additives are selected such that formation of the albuterol-aldehyde (under storage conditions and/or vaporization) will be equal or less than 0.05% of the total albuterol. Of course, contemplated co-solvents may also assist in or promote vaporization, and/or are suitable to control average particle size of the nebulized formulation.

[0040] It is further generally contemplated that the thermo-nebulizable formulations will have a chemical composition that allows thermo-nebulization of the formulation without destruction of the pharmaceutical agent. In most cases, the thermo-nebulizable formulation will include or be a low-molecular weight (i.e., average molecular weight between 200 and 600) polyol, typically in a total amount of between 70-98 vol% and more typically between 80-92 vol% of the formulation. In especially preferred aspects, the polyol is propylene glycol (also known as 1,2,-propanediol, or 1 ,2-dihydroxypropane; CAS 57-55-6) and/or glycerin (also known as 1,2,3-Propanetriol; CAS 56-81-5), and/or low-molecular weight polyethylene glycol (e.g., PEG400), and may be present in the thermo-nebulizable formulation in an amount of between 84 ⁺/_ 2 vol%. While not limiting to the inventive subject matter, the inventors contemplate that the polyol compounds in the thermo-nebulizable formulation will have one or more beneficial effects that increase the potency of the drug, and/or reduce the administered quantities. Among other things, low molecular weight polyols are known to have moderate surfactant properties, which not only may help form smaller average particle size via reduced surface tension (and as such allow deeper delivery to the lung at larger overall surface), but also provide lipophilicity to the formulation. An increased lipophilicity is thought to assist in delivery to and/or contact of the beta2 -receptor agonist to the beta2 receptor that is located in a hydrophobic environment of the plasmalemma membrane. In still further contemplated aspects, it is also noted that propylene glycol (and to some extent also other low-molecular weight polyols) exhibit significant antibiotic effect (e.g., J Exp Med 85(6); May 31 , 1947; Acta Derm Venereol. 1991 ;71 (2) : 148-50), which may be particularly advantageous when nebulized and administered to a patient that has a pulmonary infection.

[0041] The remainder of the thermo-nebulizable formulation will be water or aqueous solution that may further include additional solvents, and the thermo-nebulizable formulation will be formulated as a single phase solution. Additional components in the thermo- nebulizable formulation may include mucolytic compositions (e.g., 3-iodo-l ,2-propanediol or iodinated glycerol) as previously reported in EP941083B, or asymmetric phospholipids one or more glycerol fatty acid esters as described in US2003/0232019, both of which are incorporated by reference herein.

[0042] Therefore, particularly preferred liquid formulations will include one or more low- molecular weight polyols (e.g., propylene glycol, glycerol, and/or PEG400) in a total amount of between 80-92 vol% and a beta2 -receptor agonist bronchodilator at a concentration of between 0.25 mg/ml and 5.0 mg/ml (and optionally a corticosteroid). As already noted above, contemplated formulations may include one or more short-acting agonists (e.g., albuterol, albuterol sulfate, levalbuterol, terbutaline, pirbuterol, procaterol, clenbuterol, metaproterenol, fenoterol, bitolterol mesylate, ritodrine, ipratropium bromide, and/or isoprenaline), and/or a long-acting agonist (e.g., almeterol, formoterol, bambuterol, clenbuterol, olodaterol and indacaterol), and where desired additional surfactant(s) and/or co-solvent(s). While not limiting to the inventive subject matter, an exemplary formulation (see examples below) will include the low-molecular weight polyol is present in an amount of between 84 ⁺/_ 2 vol%, and the beta2 -receptor agonist bronchodilator at a concentration of 0.85 /_ 0.2 mg/ml.

[0043] As noted above, contemplated formulations will be preferably provided in a container that is sized and configured to retain sufficient solution for vaporization for at least two, more typically at least five, even more typically at least ten administration cycles (e.g., each using between 5-20 inhalations), while allowing the albuterol or other drug in the solution to maintain chemically stable. Such formulations will most preferably be used in a hand-held thermal vaporizer that is configured to allow multiple independent loss-free (at least 90%, and more typically at least 95% of the nebulized formulation is inhaled) and intermittent administrations of vaporized drug solution.

[0044] Therefore, kits are also contemplated that include a liquid formulation in a container that comprises the therapeutic drug (typically beta2 -receptor agonist bronchodilator and/or corticosteroid) in a thermo-nebulizable carrier. In most preferred aspects, the container is sized and dimensioned for use in an on-demand thermal nebulizer (typically completely insertable into hand-held on-demand thermal nebulizer), wherein the liquid formulation is present in the container in a volume suitable for at least ten (more typically at least 20, even more typically at least 100, and most typically at least 250) nebulization cycles.

[0045] As can be taken from the present disclosure, contemplations, and experimental data, the inventors especially contemplate various uses of low-molecular weight polyols as thermo- nebulizable carrier for a beta2 -receptor agonist bronchodilator (and/or corticosteroid) to so reduce the administered dosage of the beta2 -receptor agonist bronchodilator (and/or corticosteroid) formulation while maintaining a desired functional response for the beta2- receptor agonist bronchodilator. Therefore, and viewed from yet another perspective, the inventors also contemplate use of a thermal nebulizer to reduce the administered dosage of a beta2 -receptor agonist bronchodilator (and/or corticosteroid) while maintaining the functional response for the beta2 -receptor agonist bronchodilator (and/or corticosteroid), wherein the thermal nebulizer uses a low-molecular weight polyol in a formulation as thermo-nebulizable carrier for a beta2 -receptor agonist bronchodilator. With respect to suitable beta2 -receptor agonist bronchodilators, thermo-nebulizable carriers, polyols, and thermal nebulizers, the same considerations as already provided above apply.

[0046] In one exemplary use scenario of the inventive subject matter, two adult patients with advanced COPD were administered (upon informed consent in an off-label treatment regimen) albuterol via a commercially available thermal nebulizer. 1.5 ml of the thermo- nebulizable was formulated from 0.25 ml of 0.5% (5mg/ml) Albuterol Sulphate Inhalation Solution (commercially available from Baush & Lomb) with 1.25 ml Proplyene Glycol USP and administered in an on-demand loss free manner over 15 inhalations (nebulization cycles) for a total dose of about 67 meg as shown in Figure 1. Results were verified by spirometric testing at baseline and at regular intervals. As can be seen from the data in Figure 1, a control experiment with propylene glycol (I) did not have any effect on FEV1, while albuterol administration in a solution as described above produced a significant improvement in functional response after 20 inhalations from the thermo-nebulizer. A later administration with the same patient using 30 inhalations (albeit at a substantially higher quantity of administered albuterol) using a metered dose inhaler provided a similar but less pronounced functional response. In yet another administration using a mechanical (piston) nebulizer from a saline solution, functional response was obtained after 20 inhalations. Graphs I-VI of Figures 2A-2F show the data of Figure 1 in a plotted form.

[0047] Viewed from another perspective, Figure 3 compares and contrasts results from the thermal nebulizer (Aer Devices) treatment with treatment results using an MDI and a mechanical (piston) nebulizer. Once again, it can be clearly taken from the data that all modalities provide a desirable functional response, with the results most pronounced using the thermal nebulizer as compared to administration via MDI or mechanical nebulizer, which is particularly remarkable considering the substantially reduced administered quantity of albuterol using the thermal nebulizer (see also Table 1 above for administered quantities). Indeed, the total administered quantity for the thermal nebulizer is approximately l/36^th of the quantity used via mechanical nebulizer, and about l/8^th of the quantity used via MDI. Finally, Figure 4 graphically illustrates change in FEV1 achieved with the different modalities as compared to inhaled dosage of the drug (here: albuterol). Note that the calculation of inhaled quantities using the mechanical nebulizer in Figure 4 is based on five successive inhalations of nebulized commercially available solution (at 2500mcg/ampoule) per bar and average inhalation volume. Thus, while one administration cycle is 2500 meg, only a portion is inhaled while the remainder is continuously produced and vented into the atmosphere.

[0048] Thus, specific embodiments and methods of multi-use albuterol maintenance therapy formulations and devices therefor have been disclosed. It should be apparent, however, to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the spirit of the appended claims.

Claims

|. Use of a low-molecular weight polyol as thermo-nebulizable carrier for a beta2-receptor agonist bronchodilator to reduce an administered dosage of the beta2 -receptor agonist bronchodilator formulation while maintaining a desired functional response for the beta2- receptor agonist bronchodilator.

2. The use of claim 1 wherein the thermo-nebulizable carrier comprises a low-molecular weight polyol in an amount of between 80-92 vol% of the formulation.

3. The use of any of the preceding claims wherein the thermo-nebulizable carrier comprises at least one of propylene glycol, glycerol, and PEG400 (polyethylene glycol) in a total amount of between 80-92 vol% of the formulation.

4. The use of any one of claims 1-3 wherein the beta2 -receptor agonist bronchodilator is a short-acting agonist selected from the group consisting of albuterol, albuterol sulfate, levalbuterol, terbutaline, pirbuterol, procaterol, clenbuterol, metaproterenol, fenoterol, bitolterol mesylate, ritodrine, ipratropium bromide, and isoprenaline.

5. The use of any one of claims 1-3 wherein the beta2 -receptor agonist bronchodilator is a long-acting agonist selected from the group consisting of almeterol, formoterol, bambuterol, clenbuterol, olodaterol and indacaterol.

6. The use of any one of claims 1-3 wherein the beta2 -receptor agonist bronchodilator is albuterol or albuterol sulfate.

7. The use of any of the preceding claims wherein the beta2 -receptor agonist bronchodilator is present in the formulation at a concentration of between 0.25 mg/ml and 5.0 mg/ml.

8. The use of claim 1 wherein the low-molecular weight polyol is propylene glycol and wherein the beta2 -receptor agonist bronchodilator is albuterol.

9. The use of claim 8 wherein the propylene glycol is present in an amount of between 80- 92 vol% of the formulation and wherein the albuterol is present in the formulation at a concentration of between 0.25 mg/ml and 5.0 mg/ml.

10. Use of a thermal nebulizer to reduce an administered dosage of a beta2 -receptor agonist bronchodilator while maintaining functional response for the beta2 -receptor agonist bronchodilator, wherein the thermal nebulizer uses a low-molecular weight polyol in a formulation as thermo-nebulizable carrier for a beta2 -receptor agonist bronchodilator.

11. The use of claim 10 wherein the administered dosage is reduced from 2500 meg per administration cycle via a mechanic nebulizer to less than 100 meg per administration cycle via a thermal nebulizer.

12. The use of claim 10 wherein the administered dosage is reduced from 540 meg per

administration cycle via a metered dose inhaler to less than 100 meg per administration cycle via a thermal nebulizer.

13. The use of any one of claims 10-12 wherein the functional response is an improvement of at least 15% in FEVl .

14. The use of any one of claims 10-14 wherein the thermal nebulizer is a hand-held on- demand thermal nebulizer.

15. The use of any one of claims 10-14 wherein the beta2 -receptor agonist bronchodilator is a short-acting agonist.

16. The use of any one of claims 10-15 wherein the beta2 -receptor agonist bronchodilator is albuterol or ipratropium bromide.

17. The use of any one of claims 10-16 wherein the low-molecular weight polyol is at least one of propylene glycol, glycerol, and PEG400 (polyethylene glycol) and present in a total amount of between 80-92 vol% of the formulation.

18. The use of any one of claims 10-17 wherein the administered dosage of a beta2 -receptor agonist bronchodilator is between 50-100 meg.

19. The use of any claim 10 wherein the low-molecular weight polyol is propylene glycol, wherein the beta2 -receptor agonist bronchodilator is albuterol, and wherein the functional response is an improvement of at least 15% in FEV1 after administration of the beta2- receptor agonist bronchodilator in an amount of between 50-100 meg.

20. A liquid formulation comprising a low-molecular weight polyol in an amount of between 80-92 vol% and a beta2-receptor agonist bronchodilator at a concentration of between 0.25 mg/ml and 5.0 mg/ml.

21. The liquid formulation of claim 20 wherein the low-molecular weight polyol is at least one of propylene glycol, glycerol, and PEG400.

22. The liquid formulation of any one of claims 20-21 wherein the beta2 -receptor agonist bronchodilator is a short-acting agonist selected from the group consisting of albuterol, albuterol sulfate, levalbuterol, terbutaline, pirbuterol, procaterol, clenbuterol, metaproterenol, fenoterol, bitolterol mesylate, ritodrine, ipratropium bromide, and isoprenaline.

23. The liquid formulation of any one of claims 20-21 wherein the beta2 -receptor agonist bronchodilator is a long-acting agonist selected from the group consisting of almeterol, formoterol, bambuterol, clenbuterol, olodaterol, and indacaterol.

24. The liquid formulation of any one of claims 20-23 wherein the liquid formulation further comprises at least one of a surfactant and a co-solvent.

25. The liquid formulation of any one of claims 20-24 wherein the low-molecular weight polyol is present in an amount of between 84 ⁺/_ 2 vol%.

26. The liquid formulation of any one of claims 20-25 wherein the beta2 -receptor agonist bronchodilator is present at a concentration of 0.85 /_ 0.2 mg/ml.

27. A kit comprising:

a liquid formulation in a container;

wherein the liquid formulation comprises a beta2 -receptor agonist bronchodilator in a thermo-nebulizable carrier; and

wherein the container is sized and dimensioned for use in an on-demand thermal nebulizer, and wherein the liquid formulation is present in the container in a volume suitable for at least ten nebulization cycles.

28. The kit of claim 27 wherein the container has a volume of between 1-5 ml.

29. The kit of any one of claims 27-28 wherein the container is configured to allow insertion into a hand-held on-demand thermal nebulizer.

30. The kit of any one of claims 27-29 wherein the container is configured as a cartomizer container or a clearomizer container.

31. The kit of any one of claims 27-29 wherein the container is configured as an atomizer container.

32. The kit of any one of claims 27-31 wherein the thermo-nebulizable carrier comprises at least one of propylene glycol, glycerol, and PEG400 (polyethylene glycol) in a total amount of between 80-92 vol% of the formulation.

33. The kit of any one of claims 27-32 wherein the beta2 -receptor agonist bronchodilator is a short-acting agonist.

34. The kit of claim 33 wherein the beta2 -receptor agonist bronchodilator is albuterol or ipratropium bromide.

35. A hand-held thermal nebulizer for intermittent and on-demand thermo-nebulization of a pharmaceutical formulation, comprising:

a heating filament fluidly coupled to a reservoir suitable to contain the pharmaceutical formulation for thermo-nebulization;

an electronic circuit configured to record individual and/or cumulative on-demand thermo-nebulization; and

an output modality configured to provide an indication of the individual and/or

cumulative on-demand thermo-nebulization.

36. The hand-held thermal nebulizer of claim 35 configured as a pen sized thermal nebulizer, and wherein the reservoir has a volume suitable to contain the pharmaceutical formulation in an amount sufficient for at least three distinct administration cycles.

37. The hand-held thermal nebulizer of any one of claims 35-36 wherein the output modality comprises a display and/or a data port configured for electronic transfer of the indication.

38. The hand-held thermal nebulizer of any one of claims 35-37 wherein the pharmaceutical formulation comprises a low-molecular weight polyol and a beta2 -receptor agonist bronchodilator.

39. The hand-held thermal nebulizer of any one of claims 35-38 wherein the pharmaceutical formulation comprises at least one of propylene glycol and glycerol as a low-molecular weight polyol and a beta2 -receptor agonist bronchodilator.

40. The hand-held thermal nebulizer of any one of claims 35-39 wherein the pharmaceutical formulation comprises albuterol as a beta2 -receptor agonist bronchodilator.

41 . A method of increasing potency of a drug in a drug formulation, wherein the drug is a beta2 -receptor agonist bronchodilator, and wherein the potency is with respect to a functional response of a patient to the drug, the method comprising a step of:

combining the beta2 -receptor agonist bronchodilator with a thermo-nebulizable

carrier to so form a thermo-nebulizable solution.

42. The method of claim 41 wherein the increased potency requires administration of less than 20% of the administered dose for the same functional response as compared to administration of the drug when administered via metered dose inhaler.

43. The method of claim 41 wherein the increased potency requires administration of less than 4% of the administered dose for the same functional response as compared to administration of the drug when administered via a mechanical vaporizer.

44. The method of any one of claims 41-43 wherein the thermo-nebulizable solution

comprises a low-molecular weight polyol in an amount of between 80-92 vol% of the formulation.

45. The method of any one of claims 41-43 wherein the thermo-nebulizable carrier comprises at least one of propylene glycol, glycerol, and PEG400 (polyethylene glycol) in a total amount of between 80-92 vol% of the formulation.

46. The method of any one of claims 41-45 wherein the beta2 -receptor agonist bronchodilator is a short-acting agonist selected from the group consisting of albuterol, albuterol sulfate, levalbuterol, terbutaline, pirbuterol, procaterol, clenbuterol, metaproterenol, fenoterol, bitolterol mesylate, ritodrine, ipratropium bromide, and isoprenaline.

47. The method of any one of claims 41-46 wherein the beta2 -receptor agonist bronchodilator is albuterol.

48. The method of any one of claims 41-47 wherein the beta2 -receptor agonist bronchodilator is present in the formulation at a concentration of between 0.25 mg/ml and 5.0 mg/ml.

49. A method of reducing total administered quantity of a drug to a patient while maintaining a predetermined functional response in the patient, wherein the drug is a beta2 -receptor agonist bronchodilator, and wherein the reduced total administered quantity of the drug is relative to that of the drug when administered via a mechanic nebulizer at a dosage for the same functional response, the method comprising:

administering a reduced total administered quantity of the beta2 -receptor agonist bronchodilator using a thermo-nebulizer from a thermo-nebulizable solution.

50. The method of claim 49 wherein the reduced quantity is less than 20% of the quantity of the drug for the same functional response as compared to administration of the drug when administered via metered dose inhaler.

51. The method of claim 49 wherein the reduced quantity is less than 4% of the quantity of the drug for the same functional response as compared to administration of the drug when administered via a mechanical vaporizer.

52. The method of any one of claims 49-51 wherein the thermo-nebulizable solution

53. The method of any one of claims 49-52 wherein the thermo-nebulizable carrier comprises at least one of propylene glycol, glycerol, and PEG400 (polyethylene glycol) in a total amount of between 80-92 vol% of the formulation.

54. The method of any one of claims 49-53 wherein the beta2 -receptor agonist bronchodilator is a short-acting agonist selected from the group consisting of albuterol, albuterol sulfate, levalbuterol, terbutaline, pirbuterol, procaterol, clenbuterol, metaproterenol, fenoterol, bitolterol mesylate, ritodrine, ipratropium bromide, and isoprenaline.

55. The method of any one of claims 49-54 wherein the beta2 -receptor agonist bronchodilator is albuterol.

56. The method of any one of claims 49-55 wherein the beta2 -receptor agonist bronchodilator is present in the formulation at a concentration of between 0.25 mg/ml and 5.0 mg/ml.

57. A method of reducing a side effect of a beta2 -receptor agonist bronchodilator in a patient while maintaining a predetermined functional response in the patient, wherein the reduced side effect of the drug is relative to that of the drug when administered via a mechanic nebulizer at a dosage for the same functional response, the method comprising:

administering the beta2 -receptor agonist bronchodilator using a thermo-nebulizer from a thermo-nebulizable formulation in a quantity to achieve the predetermined functional response in the patient.

58. The method of claim 57 wherein the side effect is selected form the group consisting of tremor, anxiety, headache, muscle cramps, dry mouth, palpitation, and tachycardia.

59. The method of any one of claims 57-58 wherein the thermo-nebulizer is a hand-held on- demand thermo-nebulizer.

60. The method of any one of claims 57-59 wherein the functional response is an improvement of at least 15% in FEV1.

61. The method of any one of claims 57-60 wherein an administered dosage by the thermo- nebulizer is less than 100 meg per administration cycle.

62. The method of any one of claims 57-61 wherein the step of administering is performed without loss of nebulized formulation.