Salbutamol delivery compositions, devices and methods

Abstract

Disclosed are pharmaceutical compositions comprising a vehicle comprising at least 1234ze(E) and ethanol and at least one pharmaceutically active compound, and devices, methods, and systems using the same.

Description

Technical Field

[0001] This invention relates to drug delivery compositions, systems, apparatus, and methods. In a particular aspect, this invention relates to pharmaceutical aerosol compositions, methods, and apparatus for the quantitative delivery of salbutamol. Background Technology

[0002] Metered-dose inhalers (MDIs) have long been used to deliver medications, such as bronchodilators and steroids, to the site of treatment in patients who require it. Compared to oral administration of bronchodilators, inhalation therapy using MDIs generally has the advantages of a relatively rapid onset of action and a relatively low incidence of systemic side effects.

[0003] MDIs can be used to deliver drugs in dissolved or suspended form. Typically, when an MDI is activated, it uses a propellant with a relatively high vapor pressure to carry and expel nebulized droplets containing the API into the respiratory tract. The propellant / carrier used for the active pharmaceutical ingredient (sometimes referred to herein as the "API") must be safe for patient use and pharmaceutically acceptable. APIs delivered via MDIs are typically provided as a suspension of particles dispersed within a carrier, which facilitates the formation of the suspension and / or otherwise carries the active ingredient.

[0004] Generally, there are some challenges in providing new metered-dose inhalers, especially those based on suspensions. For example, while delivering APIs as fine particles suspended in the propellant is advantageous, these particles tend to aggregate and / or flocculate. This issue can affect the effectiveness of MDIs. Typically, users shake the MDI device before use to establish suspension. However, in some cases, the suspension may remain suspended for too short a time without flocculation and / or aggregation, which can negatively impact the efficacy of delivering the active ingredient as intended. One factor influencing the tendency for flocculation and / or aggregation is the amount of API in the suspension; increasing the amount of API tends to exacerbate the flocculation / aggregation problem. Therefore, the most common approach to overcome this problem to date has been to require users to activate the MDI more than once (usually twice) to deliver the desired dose to the target area, thus allowing for a lower amount of active ingredient in the carrier. For example, by requiring users to activate the MDI twice to deliver the desired dose, the amount of active ingredient suspended in the carrier can be reduced by 50%, thereby reducing the flocculation / aggregation problem.

[0005] The applicant has recognized that requiring more than one activation of the MDI to deliver the desired dose can have adverse consequences. For example, with existing systems and methods, if the user does not carefully read the instructions and / or forgets them and only activates the MDI once, only half the desired dose may be delivered. Therefore, one object of the present invention is to develop a carrier that avoids flocculation / aggregation problems and other MDI problems while providing an increased concentration of the active ingredient carried in the suspension. Achieving this result is a significant challenge because numerous performance properties must be achieved simultaneously with relatively high concentrations of active ingredient.

[0006] Carrier properties that may affect the performance of an MDI may include an appropriate boiling point and vapor pressure, allowing it to liquefy in a closed container at room temperature, but generating sufficiently high pressure to deliver the drug as a nebulized formulation even at lower ambient temperatures when the MDI is activated. Furthermore, the carrier should have low acute and chronic toxicity. It should exhibit high chemical stability in contact with the drug, container, and metallic and non-metallic components of the MDI device, and have a low tendency to extract low molecular weight substances from any elastomeric materials in the MDI device. Preferably, the carrier is also capable of maintaining the drug (including relatively high concentrations) in a stable suspension or dispersion for a sufficient time to allow for reproducible drug delivery during use. When the drug is suspended in the carrier, the density of the liquid carrier is preferably similar to that of the solid drug to avoid rapid settling or floating of drug particles in the liquid. Finally, the carrier should not pose a significant flammability risk to the patient during use. Specifically, it should form a non-flammable or low-flammability mixture when mixed with air in the respiratory tract. Ideal environmental characteristics, such as low GWP and low ODP, are usually also very desirable.

[0007] U.S. Patent 9,308,199, assigned to the assignee of this application, describes the use of fluoroolefins, preferably hydrofluoroolefins (HFOs), as pharmaceutically acceptable carriers that overcome the environmental drawbacks of CFCs, HFCs, and HCFCs mentioned above. Tetrafluoropropylene, including 1,3,3,3-tetrafluoropropylene (HFO-1234ze) and 2,3,3,3-tetrafluoropropylene (HFO-1234yf), is disclosed as a preferred embodiment.

[0008] WO2023 / 039103 mentions that HFO has been proposed as a propellant for MDIs, but also notes that no MDI product using HFO as a propellant has been successfully developed or commercialized. The '103 publication discloses an MDI formulation containing greater than 70% by weight HFO-1234ze(E), ethanol, and at least one active pharmaceutical ingredient (API). The disclosed amount of ethanol used in the '103 formulation ranges from as low as 0.1% by weight to as high as 20%.

[0009] Asthma is a condition frequently treated with moderately invasive diuretics (MDIs). Asthma has been described as a chronic disease involving inflammation of the lung's airways and bronchial hyperresponsiveness, resulting in a clinical presentation of usually reversible lower airway obstruction. The pathophysiology of asthma or related diseases involves bronchoconstriction caused by bronchospasm and airway inflammation accompanied by mucosal edema. Treatment of asthma and other related diseases, including chronic obstructive pulmonary disease (COPD), involves the administration of β-2 agonists, also known as β-2-adrenergic receptor agonists. These β-2-adrenergic receptor agonists are known to provide bronchodilation to patients, thereby relieving dyspnea symptoms. More specifically, β-2-adrenergic receptor agonists have been shown to increase the conductance of potassium channels in airway muscle cells, leading to membrane hyperpolarization and relaxation. Salbutamol, a short-acting β-2-adrenergic receptor agonist, has been recommended and used to relieve acute asthma symptoms.

[0010] Despite the disclosures mentioned above, the applicant recognizes the need for delivery compositions, systems, devices, and methods for salbutamol that simultaneously provide relatively low ozone depletion potential, relatively low global warming potential, and the ability to maintain the API at substantially relatively high concentrations in stable suspensions or stable dispersions for sufficient time to allow for repeatable and accurate delivery of the drug in use. Summary of the Invention

[0011] The applicant has found that the pharmaceutical compositions of the present invention and their use in MDI and inhalation delivery methods can overcome many of the disadvantages of existing compositions and / or meet many of the aforementioned needs.

[0012] This invention includes pharmaceutical compositions comprising:

[0013] a. Fine particles of salbutamol sulfate;

[0014] b. A carrier in which fine particles of the salbutamol sulfate are suspended, the carrier comprising: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); and (ii) more than 2% by weight to less than 4% by weight of ethanol.

[0015] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 1A.

[0016] This invention includes pharmaceutical compositions that are substantially composed of:

[0017] a. Fine particles of salbutamol sulfate;

[0018] b. A carrier in which fine particles of the salbutamol sulfate are suspended, the carrier comprising: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); and (ii) more than 2% by weight to less than 4% by weight of ethanol.

[0019] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 1B.

[0020] This invention includes pharmaceutical compositions comprising:

[0021] a. Fine particles of salbutamol sulfate;

[0022] b. A carrier in which fine particles of the salbutamol sulfate are suspended, the carrier comprising: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); (ii) more than 2% by weight to less than 4% by weight of ethanol; and (iii) optionally one or more excipients selected from the group consisting of: suspension forming aids, suspension stabilizers, salbutamol stabilizers, and combinations of two or more of these.

[0023] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 1C.

[0024] This invention includes pharmaceutical compositions comprising:

[0025] a. Fine particles of salbutamol;

[0026] b. A carrier in which fine particles of the salbutamol are suspended, the carrier comprising: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); and (ii) more than 2% by weight to less than 4% by weight of ethanol.

[0027] For convenience, the pharmaceutical composition described in this paragraph is referred to as Pharmaceutical Composition 1D.

[0028] This invention includes pharmaceutical compositions that are substantially composed of:

[0029] a. Fine particles of salbutamol;

[0030] b. A carrier in which fine particles of the salbutamol are suspended, the carrier comprising: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); (ii) more than 2% by weight to less than 4% by weight of ethanol; and (iii) oleic acid.

[0031] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 1E.

[0032] This invention includes pharmaceutical compositions comprising:

[0033] a. Fine particles of salbutamol;

[0034] b. A carrier in which fine particles of the salbutamol are suspended, the carrier comprising: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); and (ii) more than 2% by weight to less than 4% by weight of ethanol.

[0035] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 1F.

[0036] This invention includes pharmaceutical compositions comprising:

[0037] a. Fine particles of salbutamol sulfate;

[0038] b. A carrier in which fine particles of the salbutamol sulfate are suspended, the carrier comprising: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); (ii) more than 2% by weight to less than 4% by weight of ethanol; and (iii) oleic acid.

[0039] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 2A.

[0040] This invention includes pharmaceutical compositions that are substantially composed of:

[0041] a. Fine particles of salbutamol sulfate;

[0042] b. A carrier in which fine particles of the salbutamol sulfate are suspended, the carrier comprising: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); (ii) more than 2% by weight to less than 4% by weight of ethanol; and (iii) oleic acid.

[0043] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 2B.

[0044] This invention includes pharmaceutical compositions comprising:

[0045] a. Fine particles of salbutamol sulfate;

[0046] b. A carrier in which fine particles of the salbutamol sulfate are suspended, the carrier comprising: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); (ii) more than 2% by weight to less than 4% by weight of ethanol; and (iii) at least oleic acid and optionally one or more additional excipients selected from the group consisting of: suspension forming aids, suspension stabilizers, salbutamol stabilizers, and combinations of two or more of these.

[0047] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 2C.

[0048] This invention includes pharmaceutical compositions comprising:

[0049] a. Fine particles of salbutamol sulfate;

[0050] b. A carrier in which fine particles of the salbutamol sulfate are suspended, the carrier comprising: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); (ii) more than 2% by weight to less than 4% by weight of ethanol; and more than 0.005% by weight to 0.015% by weight of oleic acid.

[0051] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 2D.

[0052] This invention includes pharmaceutical compositions that are substantially composed of:

[0053] a. Fine particles of salbutamol sulfate;

[0054] b. A carrier in which fine particles of the salbutamol sulfate are suspended, the carrier comprising: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); (ii) more than 2% by weight to less than 4% by weight of ethanol; and more than 0.005% by weight to 0.015% by weight of oleic acid.

[0055] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 2E.

[0056] This invention includes pharmaceutical compositions comprising:

[0057] a. Fine particles of salbutamol sulfate;

[0058] b. A carrier in which fine particles of the salbutamol sulfate are suspended, the carrier comprising: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); (ii) more than 2% by weight to less than 4% by weight of ethanol; and more than 0.005% by weight to 0.015% by weight of oleic acid and optionally one or more additional excipients selected from the group consisting of: suspension forming aids, suspension stabilizers, salbutamol stabilizers, and combinations of two or more of these.

[0059] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 2F.

[0060] This invention includes pharmaceutical compositions comprising:

[0061] a. Fine particles of salbutamol;

[0062] b. A carrier in which fine particles of the salbutamol are suspended, the carrier comprising: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); (ii) more than 2% by weight to less than 4% by weight of ethanol; and (iii) oleic acid.

[0063] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 2G.

[0064] This invention includes pharmaceutical compositions comprising:

[0065] a. Fine particles of salbutamol sulfate, ranging from approximately 2.5 mg / mL to less than approximately 4.5 mg / mL;

[0066] b. A carrier in which fine particles of the salbutamol sulfate are suspended, the carrier comprising: (i) greater than about 95% by weight to less than 99% by weight of HFO-1234ze(E); and (ii) greater than 1% by weight to less than about 5% by weight of ethanol. For convenience, the pharmaceutical composition according to this paragraph is referred to as pharmaceutical composition 3A.

[0067] This invention includes pharmaceutical compositions that are substantially composed of:

[0068] a. Fine particles of salbutamol sulfate, ranging from approximately 2.5 mg / mL to less than approximately 4.5 mg / mL;

[0069] b. A carrier in which fine particles of the salbutamol sulfate are suspended, the carrier comprising: (i) more than about 95% by weight to less than 99% by weight of HFO-1234ze(E); and (ii) more than 1% by weight to less than about 5% by weight of ethanol.

[0070] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 3B.

[0071] This invention includes pharmaceutical compositions comprising:

[0072] a. Fine particles of salbutamol sulfate at a concentration of approximately 2.5 mg / mL to approximately 4.5 mg / mL;

[0073] b. A carrier in which fine particles of salbutamol sulfate are suspended, the carrier comprising: (i) more than about 95% by weight to less than 99% by weight of HFO-1234ze(E); (ii) more than 1% by weight to less than about 5% by weight of ethanol; and (iii) optionally one or more excipients selected from the group consisting of: suspension forming aids, suspension stabilizers, salbutamol stabilizers, and combinations of two or more of these.

[0074] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 3C.

[0075] This invention includes pharmaceutical compositions comprising:

[0076] a. Fine particles of salbutamol sulfate at a concentration of approximately 2.5 mg / mL to approximately 4.5 mg / mL;

[0077] b. A carrier in which fine particles of salbutamol sulfate are suspended, the carrier comprising: (i) more than about 95% by weight to less than 99% by weight of HFO-1234ze(E); (ii) more than 1% by weight to less than about 5% by weight of ethanol; and (ii) more than 0.005% by weight to 0.015% by weight of oleic acid.

[0078] For convenience, the pharmaceutical composition described in this paragraph is referred to as Pharmaceutical Composition 3D.

[0079] This invention includes pharmaceutical compositions that are substantially composed of:

[0080] a. Fine particles of salbutamol sulfate at a concentration of approximately 2.5 mg / mL to approximately 4.5 mg / mL;

[0081] b. A carrier in which fine particles of salbutamol sulfate are suspended, the carrier comprising: (i) more than about 95% by weight to less than 99% by weight of HFO-1234ze(E); (ii) more than 1% by weight to less than about 5% by weight of ethanol; and (ii) more than 0.005% by weight to 0.015% by weight of oleic acid.

[0082] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 3E.

[0083] This invention includes pharmaceutical compositions comprising:

[0084] a. Fine particles of salbutamol sulfate at a concentration of approximately 2.5 mg / mL to approximately 4.5 mg / mL;

[0085] b. A carrier in which fine particles of salbutamol sulfate are suspended, the carrier comprising: (i) greater than about 95% by weight to less than 99% by weight of HFO-1234ze(E); (ii) greater than 1% by weight to less than about 5% by weight of ethanol; and (iii) greater than 0.005% by weight to 0.015% by weight of oleic acid and optionally one or more additional excipients selected from the group consisting of: suspension forming aids, suspension stabilizers, salbutamol stabilizers, and combinations of two or more of these.

[0086] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 3F.

[0087] This invention includes pharmaceutical compositions comprising:

[0088] a. Fine particles of salbutamol ranging from approximately 2.5 mg / mL to less than approximately 4.5 mg / mL;

[0089] b. A carrier in which fine particles of the salbutamol are suspended, the carrier comprising: (i) more than about 95% by weight to less than 99% by weight of HFO-1234ze(E); and (ii) more than 1% by weight to less than about 5% by weight of ethanol.

[0090] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 3G.

[0091] This invention includes pharmaceutical compositions comprising:

[0092] a. Fine particles of salbutamol sulfate at a concentration of approximately 2.5 mg / mL to approximately 3.5 mg / mL;

[0093] b. A carrier in which fine particles of the salbutamol sulfate are suspended, the carrier comprising: (i) more than about 95% by weight to less than 99% by weight of HFO-1234ze(E); (ii) more than 1% by weight to less than about 5% by weight of ethanol; and (iii) oleic acid.

[0094] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 4A.

[0095] This invention includes pharmaceutical compositions that are substantially composed of:

[0096] a. Fine particles of salbutamol sulfate at a concentration of approximately 2.5 mg / mL to approximately 3.5 mg / mL;

[0097] b. A carrier in which fine particles of the salbutamol sulfate are suspended, the carrier comprising: (i) more than about 95% by weight to less than 99% by weight of HFO-1234ze(E); (ii) more than 1% by weight to less than about 5% by weight of ethanol; and (iii) oleic acid.

[0098] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 4B.

[0099] This invention includes pharmaceutical compositions comprising:

[0100] a. Fine particles of salbutamol sulfate at a concentration of approximately 2.5 mg / mL to approximately 3.5 mg / mL;

[0101] b. A carrier in which fine particles of the salbutamol sulfate are suspended, the carrier comprising: (i) greater than about 95% by weight to less than 99% by weight of HFO-1234ze(E); (ii) greater than 1% by weight to less than about 5% by weight of ethanol; and (iii) oleic acid and optionally one or more additional excipients selected from the group consisting of: suspension forming aids, suspension stabilizers, salbutamol stabilizers, and combinations of two or more of these.

[0102] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 4C.

[0103] This invention includes pharmaceutical compositions comprising:

[0104] a. Fine particles of salbutamol sulfate at a concentration of approximately 2.5 mg / mL to approximately 3.5 mg / mL;

[0105] b. A carrier in which fine particles of salbutamol sulfate are suspended, the carrier comprising: (i) more than about 95% by weight to less than 99% by weight of HFO-1234ze(E); (ii) more than 1% by weight to less than about 5% by weight of ethanol; and (ii) more than 0.005% by weight to 0.015% by weight of oleic acid.

[0106] For convenience, the pharmaceutical composition described in this paragraph is referred to as Pharmaceutical Composition 4D.

[0107] This invention includes pharmaceutical compositions that are substantially composed of:

[0108] a. Fine particles of salbutamol sulfate at a concentration of approximately 2.5 mg / mL to approximately 3.5 mg / mL;

[0109] b. A carrier in which fine particles of salbutamol sulfate are suspended, the carrier comprising: (i) more than about 95% by weight to less than 99% by weight of HFO-1234ze(E); (ii) more than 1% by weight to less than about 5% by weight of ethanol; and (ii) more than 0.005% by weight to 0.015% by weight of oleic acid.

[0110] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 4E.

[0111] This invention includes pharmaceutical compositions comprising:

[0112] a. Fine particles of salbutamol sulfate at a concentration of approximately 2.5 mg / mL to approximately 3.5 mg / mL;

[0113] b. A carrier in which fine particles of salbutamol sulfate are suspended, the carrier comprising: (i) greater than about 95% by weight to less than 99% by weight of HFO-1234ze(E); (ii) greater than 1% by weight to less than about 5% by weight of ethanol; and (iii) greater than 0.005% by weight to 0.015% by weight of oleic acid and optionally one or more additional excipients selected from the group consisting of: suspension forming aids, suspension stabilizers, salbutamol stabilizers, and combinations of two or more of these.

[0114] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 4F.

[0115] This invention includes pharmaceutical compositions comprising:

[0116] a. Fine particles of salbutamol at a concentration of approximately 2.5 mg / mL to approximately 3.5 mg / mL;

[0117] b. A carrier in which fine particles of the salbutamol are suspended, the carrier comprising: (i) more than about 95% by weight to less than 99% by weight of HFO-1234ze(E); (ii) more than 1% by weight to less than about 5% by weight of ethanol; and (iii) oleic acid.

[0118] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 4G.

[0119] This invention includes pharmaceutical compositions in aerosol form, which comprise:

[0120] a. Fine particles of salbutamol; and

[0121] b. A carrier that carries fine particles of the salbutamol and comprises: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); and (ii) more than 1% by weight to less than 4% by weight of ethanol, wherein the amount of the salbutamol in the aerosol is about more than 150 micrograms to about 300 micrograms.

[0122] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 5A.

[0123] This invention includes pharmaceutical compositions in aerosol form, which are substantially composed of the following:

[0124] a. Fine particles of salbutamol sulfate; and

[0125] b. A carrier carrying fine particles of the salbutamol sulfate and comprising: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); and (ii) more than 1% by weight to less than 4% by weight of ethanol, wherein the amount of the salbutamol sulfate in the aerosol is about more than 150 micrograms to about 300 micrograms.

[0126] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 5B.

[0127] This invention includes pharmaceutical compositions in aerosol form, which consist of the following:

[0128] a. Fine particles of salbutamol sulfate; and

[0129] b. A carrier carrying fine particles of the salbutamol sulfate and comprising: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); (ii) more than 1% by weight to less than 4% by weight of ethanol; and (iii) optionally one or more excipients selected from the group consisting of: suspension forming aids, suspension stabilizers, salbutamol stabilizers, and combinations of two or more of these, wherein the amount of the salbutamol sulfate in the aerosol is about more than 150 micrograms to about 300 micrograms.

[0130] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 5C.

[0131] This invention includes pharmaceutical compositions in aerosol form, which comprise:

[0132] a. Fine particles of salbutamol sulfate; and

[0133] b. A carrier carrying fine particles of the salbutamol sulfate and comprising: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); (ii) more than 1% by weight to less than 4% by weight of ethanol; and (iii) more than 0.005% by weight to 0.015% by weight of oleic acid, wherein the amount of the salbutamol sulfate in the aerosol is about more than 150 micrograms to about 300 micrograms.

[0134] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 5D.

[0135] This invention includes pharmaceutical compositions in aerosol form, which are substantially composed of the following:

[0136] a. Fine particles of salbutamol sulfate; and

[0137] b. A carrier carrying fine particles of the salbutamol sulfate and comprising: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); (ii) more than 1% by weight to less than 4% by weight of ethanol; and (iii) more than 0.005% by weight to 0.015% by weight of oleic acid, wherein the amount of the salbutamol sulfate in the aerosol is about more than 150 micrograms to about 300 micrograms.

[0138] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 5E.

[0139] This invention includes pharmaceutical compositions in aerosol form, which consist of the following:

[0140] a. Fine particles of salbutamol sulfate; and

[0141] b. A carrier carrying fine particles of the salbutamol sulfate and comprising: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); (ii) more than 1% by weight to less than 4% by weight of ethanol; and (iii) more than 0.005% by weight to 0.015% by weight of oleic acid and optionally one or more excipients selected from the group consisting of: suspension forming aids, suspension stabilizers, salbutamol stabilizers, and combinations of two or more of these, wherein the amount of the salbutamol sulfate in the aerosol is about more than 150 micrograms to about 300 micrograms.

[0142] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 5F.

[0143] This invention includes pharmaceutical compositions in aerosol form, which comprise:

[0144] a. Fine particles of salbutamol; and

[0145] b. A carrier that carries fine particles of the salbutamol and comprises: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); and (ii) more than 1% by weight to less than 4% by weight of ethanol, wherein the amount of the salbutamol in the aerosol is about more than 150 micrograms to about 300 micrograms.

[0146] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 5G.

[0147] This invention includes pharmaceutical compositions in aerosol form, which comprise:

[0148] a. Fine particles of salbutamol sulfate; and

[0149] b. A carrier that carries fine particles of the salbutamol sulfate and comprises: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); (ii) more than 1% by weight to less than 4% by weight of ethanol; and (iii) oleic acid, wherein the amount of the fine particles of the salbutamol sulfate in the aerosol is about more than 150 micrograms to about 300 micrograms.

[0150] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 6A.

[0151] This invention includes pharmaceutical compositions in aerosol form, which are substantially composed of the following:

[0152] a. Fine particles of salbutamol sulfate; and

[0153] b. A carrier that carries fine particles of the salbutamol sulfate and comprises: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); (ii) more than 1% by weight to less than 4% by weight of ethanol; and (iii) oleic acid, wherein the amount of the fine particles of the salbutamol sulfate in the aerosol is about more than 150 micrograms to about 300 micrograms.

[0154] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 6B.

[0155] This invention includes pharmaceutical compositions in aerosol form, which consist of the following:

[0156] a. Fine particles of salbutamol sulfate; and

[0157] b. A carrier that carries fine particles of the salbutamol sulfate and comprises: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); (ii) more than 1% by weight to less than 4% by weight of ethanol; and (iii) oleic acid, wherein the amount of the fine particles of the salbutamol sulfate in the aerosol is about more than 150 micrograms to about 300 micrograms.

[0158] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 6C.

[0159] This invention includes pharmaceutical compositions in aerosol form, which comprise:

[0160] a. Fine particles of salbutamol sulfate; and

[0161] b. A carrier carrying fine particles of the salbutamol sulfate and comprising: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); (ii) more than 1% by weight to less than 4% by weight of ethanol; and (iii) more than 0.005% by weight to 0.015% by weight of oleic acid, wherein the amount of the fine particles of the salbutamol sulfate in the aerosol is about more than 150 micrograms to about 300 micrograms.

[0162] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 6D.

[0163] This invention includes pharmaceutical compositions in aerosol form, which are substantially composed of the following:

[0164] a. Fine particles of salbutamol sulfate; and

[0165] b. A carrier carrying fine particles of the salbutamol sulfate and comprising: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); (ii) more than 1% by weight to less than 4% by weight of ethanol; and (iii) more than 0.005% by weight to 0.0215% by weight of oleic acid, wherein the amount of the fine particles of the salbutamol sulfate in the aerosol is about more than 150 micrograms to about 300 micrograms.

[0166] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 6E.

[0167] This invention includes pharmaceutical compositions in aerosol form, which consist of the following:

[0168] a. Fine particles of salbutamol sulfate; and

[0169] b. A carrier carrying fine particles of salbutamol sulfate and comprising: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); (ii) more than 1% by weight to less than 4% by weight of ethanol; and (iii) more than 0.005% by weight to 0.015% by weight of oleic acid and optionally one or more excipients selected from the group consisting of suspension forming aids, suspension stabilizers, salbutamol stabilizers, and combinations of two or more of these, wherein the amount of fine particles of salbutamol sulfate in the aerosol is about more than 150 micrograms to about 300 micrograms. For convenience, the pharmaceutical composition according to this paragraph is referred to as pharmaceutical composition 6F.

[0170] This invention includes pharmaceutical compositions in aerosol form, which comprise:

[0171] a. Fine particles of salbutamol; and

[0172] b. A carrier that carries fine particles of the salbutamol and comprises: (i) more than about 96% by weight to less than 98% by weight of HFO-1234ze(E); (ii) more than 1% by weight to less than 4% by weight of ethanol; and (iii) oleic acid, wherein the amount of the fine particles of the salbutamol in the aerosol is about more than 150 micrograms to about 300 micrograms.

[0173] For convenience, the pharmaceutical composition described in this paragraph is referred to as pharmaceutical composition 6G.

[0174] The present invention also includes a method for delivering a prescription dose of salbutamol sulfate, the method comprising:

[0175] a. Provided in an MDI comprising: (1) a carrier comprising greater than about 95% by weight and less than 99% by weight of HFO-1234ze(E); and (ii) greater than 1% by weight and less than about 5% by weight of ethanol; and (2) fine particles of salbutamol sulfate; and

[0176] b. Actuate the MDI once to produce a single aerosol spray of the salbutamol sulfate, wherein the single spray contains approximately the prescribed dose of the salbutamol sulfate.

[0177] For convenience, the method described in this paragraph is referred to as drug delivery method 1A.

[0178] The present invention also includes a method for delivering a prescribed dose of salbutamol, the method comprising:

[0179] a. Provided in an MDI comprising the pharmaceutical compositions of the present invention, including each of pharmaceutical compositions 1-6; and

[0180] b. Actuate the MDI once to produce a single aerosol spray of fine particles of salbutamol, wherein the single spray contains approximately the prescribed dose of the salbutamol.

[0181] For convenience, the method described in this paragraph is referred to as drug delivery method 1B.

[0182] The present invention also includes a method for delivering a prescription dose of salbutamol sulfate, the method comprising:

[0183] a. Provided in an MDI comprising: (1) a carrier comprising greater than about 95% by weight to less than 99% by weight of HFO-1234ze(E); and (ii) greater than 1% by weight to less than about 5% by weight of ethanol; and (2) fine particles of an API carried by said carrier, wherein said API comprises

[0184] b. Actuate the MDI once to produce a single aerosol spray of the pharmaceutical composition, wherein the single spray contains the prescribed dose, wherein the prescribed dose is about 150 micrograms to about 300 micrograms.

[0185] For convenience, the method described in this paragraph is referred to as drug delivery method 2A.

[0186] The present invention also includes a method for delivering a prescribed dose of salbutamol, the method comprising:

[0187] a. Provided in an MDI for delivering the pharmaceutical compositions of the present invention (including each of pharmaceutical compositions 1-6); and

[0188] b. Actuate the MDI once to produce a single aerosol spray of the pharmaceutical composition, wherein the single spray contains the prescribed dose, wherein the prescribed dose is an amount of about 150 micrograms to about 300 micrograms of salbutamol.

[0189] For convenience, the method described in this paragraph is referred to as drug delivery method 2B.

[0190] The present invention also includes a metered-dose inhaler (MDI) comprising:

[0191] a. container;

[0192] b. A pressurized pharmaceutical composition in a container, the pharmaceutical composition comprising: (i) greater than about 95% by weight to less than 99% by weight of HFO-1234ze(E); (ii) greater than 1% by weight to less than about 5% by weight of ethanol; and (iii) about 2.5 mg / mL to about 3.5 mg / mL of salbutamol sulfate, said salbutamol sulfate being in the form of fine particles; and

[0193] c. A normally closed valve on the container, the normally closed valve being actuated to an open position to release a predetermined volume of the pharmaceutical composition as an aerosol spray from the container.

[0194] For convenience, the MDI referred to in this section is called MDI 1A.

[0195] The present invention also includes a metered-dose inhaler (MDI) comprising:

[0196] a. container;

[0197] b. A pressurized pharmaceutical composition of the present invention in a container, comprising each of pharmaceutical compositions 1-6; and

[0198] c. A normally closed valve on the container, the normally closed valve being actuated to an open position to release a predetermined volume of the pharmaceutical composition as an aerosol spray from the container.

[0199] For convenience, the MDI referred to in this section is called MDI 1B.

[0200] The present invention also includes a metered-dose inhaler (MDI) comprising:

[0201] a. container;

[0202] b. A pressurized pharmaceutical composition in the container, the pharmaceutical composition comprising: (a) a carrier comprising more than about 95% by weight to less than 99% by weight of HFO-1234ze(E); and (ii) more than 1% by weight to less than about 5% by weight of ethanol; and (b) fine particles of salbutamol sulfate suspended in the carrier at a concentration of about 2.5 mg / mL to about 3.5 mg / mL.

[0203] For convenience, the MDI referred to in this section is called MDI 2A. Attached Figure Description

[0204] The present invention will now be described with reference to the accompanying drawings, in which:

[0205] Figure 1 This is a cross-sectional side view of an inhaler including a canister equipped with a valve, according to the present disclosure.

[0206] Figure 2 yes Figure 1 A detailed cross-sectional side view of the inhaler.

[0207] Figure 3 This is a cross-sectional side view of the metering valve used in an inhaler.

[0208] Figure 4 This is a chart showing the data from Example 1.

[0209] Figure 5 This is a chart showing the data from Example 1.

[0210] Figure 6 This is a chart showing the data from Example 1.

[0211] Figure 7 This is a chart showing the data from Example 2.

[0212] Figure 8 This is a chart showing the data from Example 2.

[0213] Figure 9 This is a chart showing the data from Example 2. Detailed Implementation

[0214] I. Definition

[0215] For the purposes of this invention, the term "about" for an amount greater than 2% by weight means that the amount of the component may vary by + / - 1% by weight.

[0216] For the purposes of this invention, the term "about" refers to an amount expressed as a weight percentage of less than 2% and greater than 1%, meaning that the amount of the component may vary by weight of + / - 0.2%.

[0217] For the purposes of this invention, the term "about" refers to an amount expressed as a weight percentage of less than 1% and greater than 0.5%, meaning that the amount of the component may vary by weight of + / - 0.1%.

[0218] For the purposes of this invention, the term "about" with respect to amounts expressed in milligrams per milliliter (mg / mL) means that the amount of the component can vary by + / - 0.05 mg / mL.

[0219] For the purposes of this invention, the term "about" in relation to a prescription dose expressed in micrograms (μg) means that the amount of the component can vary by + / - 5 μg.

[0220] For the purposes of this invention, the term "composition" is used broadly to include single-phase compositions and compositions comprising two or more phases, such as compositions comprising a continuous liquid phase and solid particles suspended or dispersed in the liquid phase, or gas phases such as those present in aerosol compositions having suspended, dispersed, and / or gaseous solid particles carried by a gas phase.

[0221] The term "pharmaceutical composition" is used herein to include any composition comprising at least one agent, ingredient, drug, compound, composition or other substance that may be used or administered to humans or animals for one or more purposes including therapeutic, pharmaceutical, pharmacological, diagnostic and preventive and immunomodulatory.

[0222] The term "fine particles" refers to particles with an average particle size of up to about 10 micrometers (10 μm).

[0223] The term "prescription dose" refers to the amount of salbutamol (including salbutamol sulfate) that an MDI manufacturer or healthcare professional is to take at a specified time.

[0224] The term “delivery dose” and its abbreviation “DD” refer to the amount of salbutamol particles contained in the volume of the composition that leaves the actuator nozzle of the MDI and can be inhaled into the patient’s lungs.

[0225] The term "fine particulate mass" and its abbreviation "FPM" refers to the dose contained in the volume of the composition, by total mass, present as a single spray from the actuator nozzle of the MDI, within the inhalable range. The dose within the inhalable range is measured in vitro as the sum of the doses delivered by the Andersen Cascade Impactor at a flow rate of 28.3 L / min in stages 2–7.

[0226] In the case of compositions containing or providing inhalable aggregates, particles, droplets, etc. (such as the compositions described herein), the term "fine particle fraction" or "FPF" refers to the ratio of the delivered material in the inhalable range to the delivered dose (i.e., the amount leaving the actuator of the delivery device (e.g., MDI)). The amount of delivered material in the inhalable range is measured in vitro as the sum of the material delivered by the Andersen Cascade Impactor at a flow rate of 28.3 L / min in stages 2–7.

[0227] As used herein, “median mass aerodynamic diameter” or “MMAD” refers to the aerodynamic diameter of an aerosol. Below this diameter, 50% of the mass of an aerosol consists of particles with an aerodynamic diameter smaller than MMAD, where MMAD is calculated according to United States Pharmacopeia (“USP”) General 601.

[0228] As used herein, the term "carrier" refers to one or more pharmacologically inert substances that provide a continuous phase in which salbutamol particles (including salbutamol sulfate particles) are suspended, and which contain components that, at normal room temperature, exert a sufficiently high vapor pressure to propel the particles from the canister of the MDI into the patient's body upon actuation of the metering valve of the MDI. Thus, the term "carrier" includes both a single component and a combination of two or more different components that form a medium in which salbutamol is suspended or otherwise carried. Therefore, the 1234ze(E) component of the carrier of the compositions of the present invention at least acts as a propellant.

[0229] The term "inhalable" typically refers to particles, aggregates, droplets, etc., that are small enough to be inhaled and reach the lung airways.

[0230] The term “delivery dose uniformity” (DDU) for pharmaceutical compositions refers to uniformity as measured by USP 601.

[0231] The terms “HFC-134a” and “R134a” refer to 1,1,1,2-tetrafluoroethane.

[0232] As used herein, the terms “HFO-1234ze(E)” and “1234ze(E)” each refer to trans-1,3,3,3-tetrafluoropropylene. Unless otherwise stated, “HFO-1234ze” and “1234ze” refer to trans-1,3,3,3-tetrafluoropropylene.

[0233] As used herein, the term "salbutamol" encompasses any and all pharmaceutically acceptable forms of salbutamol, including pharmaceutically acceptable salts of salbutamol (e.g., salbutamol sulfate) and pharmaceutically acceptable esters of salbutamol.

[0234] References to a set of defined items in this document include all such defined items, including all such items with a suffix identifier. Thus, for example, references to “pharmaceutical composition 1-22” in this document specifically refer to each of pharmaceutical compositions 1A, 1B, 1C, 1D, 1E, 1F, 2A, 2B, 2C, 2D, 2E, 2F, 2G, etc.

[0235] II. Composition

[0236] The preferred pharmaceutical compositions of the present invention include each of pharmaceutical compositions 1-22, preferably a suspension of salbutamol in a carrier containing other essential components of the composition (specifically including HFO-1234ze(E) and ethanol).

[0237] The preferred pharmaceutical compositions of the present invention, comprising each of pharmaceutical compositions 1-22, are physically stable. The preferred pharmaceutical compositions of the present invention, comprising each of pharmaceutical compositions 1-22, are chemically stable. The preferred pharmaceutical compositions of the present invention, comprising each of pharmaceutical compositions 1-22, are both physically and chemically stable.

[0238] Component concentration

[0239] Within the broad scope of this invention, the concentrations of components in the compositions of this invention can generally vary considerably. The concentration of salbutamol contained in the compositions of this invention (including each of pharmaceutical compositions 1-6) (measured in milligrams per milliliter (mg / mL)) is preferably greater than 2.5 mg / mL, or greater than about 2.5 mg / mL to less than about 5 mg / mL, or greater than about 2.5 mg / mL to less than about 4.5 mg / mL, or greater than 2.5 mg / mL to less than about 4.0 mg / mL. Preferred compositions include those identified in Tables 1A and 1B below, where the following names have the following meanings: "Comp" indicates that the composition contains the identified component; CEO indicates that the composition consists substantially of the identified component; CO indicates that the composition consists of the identified component.

[0240] Table 1A

[0241]

[0242]

[0243]

[0244] The amounts of *1234ze(E) and ethanol should be understood as being preceded by the term "about" in the table, as defined above for the relevant amounts.

[0245] Table 1B

[0246]

[0247]

[0248]

[0249] The amounts of *1234ze(E) and ethanol should be understood as being preceded by the term "about" in the table, as defined above for the relevant amounts.

[0250] For all compositions of the present invention, in addition to those defined as “comprising” “the specified components”, each of pharmaceutical compositions 1-22 may contain additional components or excipients. These components may have a variety of uses and functions, including but not limited to promoting suspension formation, stabilizing suspensions, and / or contributing to the chemical stability of salbutamol or other components.

[0251] Preferred excipients include those suitable for inhalation delivery and substantially non-degradable or non-soluble in the suspension medium, and are preferably suspension-forming aids, suspension stabilizers, salbutamol stabilizers, and combinations thereof. In certain cases, excipients are selected from the group consisting of lipids, phospholipids, carbohydrates, amino acids, organic salts, peptides, proteins, sugar alcohols, synthetic or natural polymers, surfactant materials, and combinations thereof.

[0252] For all compositions of the present invention, including each of pharmaceutical compositions 1-22, the composition comprises a suspension of designated salbutamol in HFO-1234ze(E) and ethanol, and in the presence of oleic acid. In all such compositions, including each of pharmaceutical compositions 1-22, the designated salbutamol is preferably in microparticle solid form (preferably micronized, but particle size can also be reduced by a variety of other particle size reduction techniques). As used herein, the suspension of salbutamol may also have a very small amount of dissolved particulate matter in the composition. For the compositions of the present invention, including each of pharmaceutical compositions 1-22, dissolution of salbutamol is generally undesirable. In embodiments including each of pharmaceutical compositions 1-22, minimal or nominal dissolution of salbutamol may be present, but in preferred embodiments including each of pharmaceutical compositions 1-22, substantially no measurable dissolution of salbutamol is observed.

[0253] In certain preferred forms, the compositions of the present invention, comprising each of pharmaceutical compositions 1-22, have a global warming potential (GWP) of not more than about 300, more preferably not more than about 150, not more than 75, and most preferably not more than about 10. As used herein, “GWP” is relative to carbon dioxide and measured over a 100-year time span, and its definition is given in “The Scientific Assessment of Ozone Depletion, 2002, a report of the World Meteorological Association's Global Ozone Research and Monitoring Project,” which is incorporated herein by reference.

[0254] In certain preferred embodiments, the compositions of the present invention also preferably have an ozone depletion potential (ODP) of not more than 0.05, preferably not more than 0.02, and even more preferably about zero. As used herein, the definition of “ODP” is given in “The Scientific Assessment of Ozone Depletion, 2002, A report of the World Meteorological Association's Global Ozone Research and Monitoring Project,” which is incorporated herein by reference.

[0255] III. Apparatus and Methods

[0256] This invention includes a device for delivering the compositions of the invention, including each of pharmaceutical compositions 1-22, by inhalation. In some preferred embodiments, the device of the invention includes a container, preferably an aerosol canister, containing the pressurized compositions of the invention (including each of pharmaceutical compositions 1-22) and preferably having a metered-dose dispensing valve operable between a non-dispensing position and a dispensing position. The device of the invention preferably also includes an actuator, in a preferred embodiment, comprising a housing adapted to receive the aerosol canister and defining a chamber in fluid communication with a patient interface for introducing the medication into the patient's oral cavity and / or nasal cavity, preferably in the form of a mouthpiece and / or nasal adapter. The actuator also preferably includes a nozzle block adapted to receive the valve stem of the dispensing valve, the nozzle block preferably including a channel in fluid communication with the valve stem and terminating at an orifice for guiding the medication from the valve stem into the chamber.

[0257] Using examples rather than limitations, Figure 1 One embodiment of a metered-dose inhaler 100 is shown, comprising an aerosol canister 1 equipped with a metering valve 10 (shown in its resting position). The metering valve 10 is typically secured via a cap or sleeve 11 (typically made of aluminum or an aluminum alloy), i.e., crimped onto the canister body, which is typically supplied as part of the valve assembly. One or more seals may be present between the canister body and the sleeve. Figure 1 and Figure 2 In the embodiment shown, there are two seals between the tank body 1 and the ferrule 11, such as an O-ring seal and a gasket seal.

[0258] like Figure 1As shown, the canister / valve dispenser typically includes an actuator 5, which comprises a suitable patient interface 6, such as a suction nozzle. For nasal administration, the patient interface is typically provided in a suitable form (e.g., a smaller diameter tube typically angled upwards) for delivery through the nose. The actuator is typically made of a plastic material, such as polypropylene or polyethylene. Figure 1 It can be seen that the inner wall 2 of the tank and the outer wall 101 of the portion of the metering valve 10 located inside the tank define the composition chamber 3 in which the aerosol composition 4 is contained.

[0259] Figure 1 and Figure 2 The valve 10 shown includes a metering chamber 12, which is partially defined by an inner valve body 13 through which a valve stem 14 passes. The valve stem 14 is biased outward by a compression spring 15 and slides into a sealing engagement with an inner tank seal 16 and an outer diaphragm seal 17. The valve 10 also includes a second valve body 20 in the form of a bottle vent. The inner valve body 13 (also referred to as the “main” valve body) partially defines the metering chamber 12. The second valve body 20 (also referred to as the “secondary” valve body), in addition to acting as a bottle vent, also partially defines a pre-emptive volume area or chamber.

[0260] See Figure 2 The aerosol composition 4 can enter the pre-quantity chamber 22 located between the sub-valve body 20 and the main valve body 13 from the composition chamber 3 through the annular gap 21 between the flange 23 of the sub-valve body 20 and the main valve body 13. To actuate (activate) the valve 10, the valve stem 14 relative to the tank 1... Figure 1 and Figure 2 The resting position shown is pushed inward, allowing the composition to flow from the metering chamber 12 through the side hole 19 in the valve stem and through the valve stem outlet 24 to the actuator nozzle 7, and then to the patient. When the valve stem 14 is released, the composition enters the valve 10, particularly the pre-measurement chamber 22, through the annular gap 21, and then from the pre-measurement chamber through the groove 18 in the valve stem and through the reservoir seal 16 into the metering chamber 12.

[0261] Figure 3 Another embodiment of the metering valve 102 in its resting position is shown, which differs from... Figure 1 and Figure 2The illustrated embodiment. Valve 102 has a metering chamber 112 partially defined by a metering canister 113, through which a rod 114 is biased outward by a spring 115. The rod 114 is made of two parts, which are press-fitted together before being assembled to valve 102. An internal seal 116 and an external seal 117 are provided around the rod 114, forming a sealing contact with the metering canister 113. A valve body 120, with a crimped press-fit sleeve 111, holds the aforementioned components within the valve. In use, the composition enters the metering chamber through orifices 121 and 118. When dispensing a dose, the composition travels outward from the metering chamber 112 through orifice 119.

[0262] In some embodiments, the device of the present invention is configured such that airflow due to patient inhalation is blocked or reduced near the orifice, either always or only during drug dispensing from the valve. Any such arrangement has the effect of significantly reducing the jet spray velocity compared to inhalers that allow free airflow near the nozzle block during drug dispensing.

[0263] In some embodiments, the actuator is configured such that the distance from the nozzle to the mouthpiece is about 1 cm to 15 cm, preferably 4 cm to 6 cm, wherein the diameter of the chamber / mouthpiece is 1 cm to 4 cm, or 0.5 cm to 1 cm in the case of a nasal adapter.

[0264] In some preferred but non-limiting embodiments, the actuator has an air inlet that allows the patient to inhale through a patient interface, preferably without encountering significant resistance, as the patient may experience breathing difficulties while taking the medication (e.g., during an asthma attack). However, the air inlet, such as in a mouthpiece, preferably does not concentrate the airflow into an overly narrow area, as this would result in high-velocity incoming air, causing the spray to deflect against the mouthpiece wall opposite the air inlet. In some preferred embodiments, the air inlet is located downstream of the nozzle, in and / or downstream of the turbulent flow zone. The location and orientation of the air inlet may also affect drug deposition within the chamber and mouthpiece. In one arrangement, the air inlet comprises a series of orifices and may optionally be distributed with fluid deflection structures on the chamber walls to guide air into the turbulent flow zone, allowing the air to mix with the aerosol flow. Additionally, the mouthpiece may be constructed of a porous material to allow multiple subdivided pores to provide airflow over a larger surface area.

[0265] In some embodiments, the actuator has an air inlet upstream or near the nozzle, but the inlet is blocked when the valve is actuated to release the aerosol spray. After spray release, when the aerosol flow velocity has decreased and a turbulent zone has formed, the air inlet is opened. Upon inhalation, an airflow is established from the air inlet to the mouthpiece, entraining residual aerosol spray. The actuator may include an additional air inlet downstream of the nozzle, as described above with respect to the first embodiment. These downstream air inlets do not need to be closed during aerosol spray release.

[0266] In some embodiments, a porous membrane is present to introduce air into or downstream of the turbulent zone. One advantage of using such a membrane is that air is introduced more evenly and diffusely around the circumference of the spray, thus buffering the turbulence against the walls. This reduces drug deposition within the device. The porous membrane may optionally prevent contact with contaminants or the user's lips via an additional portion of the mouthpiece. When present, it is preferred that the porous membrane material (50) does not significantly impede the patient's ability to inhale through the device. A suitable material is Whatmann No. 4 filter paper; however, other materials may also be used, such as those used for cylindrical air filters or membrane filters, or materials formed by sintering polymers. A preferred porous membrane material is a cylindrical form made by fusing small polypropylene particles together.

[0267] For certain medications, it is preferable to configure the device to reduce contact between the medication and other body parts besides the site where it is intended to come into contact with the patient. For example, medication residue deposited on the inner surface of the actuator may be touched by a finger and transferred to other body parts. In this case, the device may be configured to include one or more fluid flow deflectors to allow the spray to pass through while limiting patient contact with the inner surface of the actuator. Of course, the device may be configured for intranasal delivery. This is generally undesirable because these medications are designed for delivery to the respiratory system and may not be effective when deposited in the oropharynx and allowed to enter the digestive tract. To overcome this problem, some embodiments of the device of the present invention include providing a receiving space, commonly referred to as a spacer, in which the medication is aspirated. The spacer preferably allows for a reduced drug velocity and may also allow some propellant evaporation. The spacer can improve the performance of a metered-dose inhaler by reducing oropharyngeal deposition.

[0268] The total amount of the inventive compositions (including each of pharmaceutical compositions 1-22) contained in the canister is preferably selected such that at least a portion of the propellant in the canister remains in liquid form after a predetermined quantity of pharmaceutical dose has been delivered. The predetermined quantity of dose can be 5 to 200, 30 to 200, 60 to 200, 60 to 120, 60, 120, 200, or any other quantity. In a preferred embodiment, the total amount of the inventive compositions (including each of pharmaceutical compositions 1-22) in the canister can be 1.0 g to 30.0 g, 2.0 g to 20.0 g, or 5.0 g to 10.0 g. The total amount of the inventive compositions (including each of pharmaceutical compositions 1-22) is generally selected to be greater than the product of the predetermined dose and the metering valve volume. In some embodiments, the total amount of composition is greater than 1.1 times, greater than 1.2 times, greater than 1.3 times, greater than 1.4 times, or greater than 1.5 times the product of the predetermined dose and the metering valve volume. This helps ensure that the amount of each dose remains relatively constant throughout the lifespan of the inhaler.

[0269] Therefore, the present invention provides an inhaler, preferably a metered-dose inhaler (MDI), for treating asthma and other chronic obstructive pulmonary diseases, and for delivering a pharmaceutical composition (including each of pharmaceutical compositions 1-22) to an accessible mucosa or nasal cavity. Thus, the present invention includes a method for delivering a pharmaceutical composition (including each of pharmaceutical compositions 1-22) for the purpose of treating diseases, illnesses, and similar health-related problems in an organism (such as a human or animal), the method comprising administering to the organism requiring treatment a composition of the present invention containing a drug or other therapeutic component. In some preferred embodiments, the step of administering the composition of the present invention comprises providing an MDI containing the composition of the present invention (including each of pharmaceutical compositions 1-22), and then discharging the composition of the present invention from the MDI.

[0270] The size of the MDI metering valve, i.e. the size of the metering chamber, can vary within the scope of this invention, but can be between 200 μL (or mcl) and 400 μL, between 200 μL and 360 μL, between 200 μL and 340 μL, between 200 μL and 320 μL, or between 200 μL and 300 μL.

[0271] In some embodiments, the typical compositions of this disclosure contain at least 0.2 mg / puff (200 μg / puff) or at least 0.25 mg / puff (250 μg / puff) of salbutamol sulfate. In some embodiments, the typical compositions of this disclosure contain less than 0.4 mg / puff (400 μg / puff) of salbutamol sulfate.

[0272] In embodiments, typical compositions of this disclosure contain less than 500 μg / amplitude, up to 400 μg / amplitude, and up to 300 μg / amplitude of salbutamol sulfate. In some preferred embodiments, compositions of this disclosure contain 200 μg / amplitude to 400 μg / amplitude of salbutamol sulfate.

[0273] The present invention includes a method for forming a pharmaceutical composition having improved stability, comprising each of pharmaceutical compositions 1-22, the method comprising forming a carrier comprising not less than 96% by weight and greater than about 2% by weight and less than 5% by weight of ethanol, suspending the salbutamol in the carrier, preferably wherein the suspension has at least about 2.5% by weight and less than about 4 mg / mL of salbutamol.

[0274] The present invention includes a method for forming a pharmaceutical composition having improved stability, comprising each of pharmaceutical compositions 1-22, the method comprising forming a carrier comprising not less than 96% by weight and greater than about 2% by weight and less than 5% by weight of ethanol, suspending the salbutamol sulfate in the carrier, preferably wherein the suspension has at least about 2.5% by weight and less than about 4 mg / mL of salbutamol sulfate.

[0275] The present invention includes a method for forming a pharmaceutical composition having improved stability, comprising each of pharmaceutical compositions 1-22, the method comprising forming a carrier comprising not less than 96% by weight and greater than about 2% by weight and less than 5% by weight of ethanol, suspending the API in the carrier, the API comprising 0.25% by weight to about 0.5% by weight of salbutamol, substantially consisting of or consisting of therein.

[0276] Example

[0277] Comparative Example 1: Sulfuric acid in 100% HFO-1234ze(E) and in a mixture of HFO-1234ze(E) and ethanol The delivery dose and particle size of the salbutamol suspension were measured, wherein the nominal dose per actuation was 100 μg.

[0278] Salbutamol sulfate (API) was suspended in HFC-1234ze(E) and a mixture of HFC-1234ze(E) and ethanol in the amounts shown in Example 3 of WO2023 / 039103A1 and reported in Table C1 below. Each suspension was prepared with 1.91 mg / mL salbutamol sulfate to provide a nominal dose of 100 μg / puff. Each suspension was filled into FEP-coated canisters, coiled with 63 pL valves, and tested using a KINDEVA actuator with a 0.4 mm outlet orifice. The fine particle mass (FPM), fine particle fraction (FPF), and delivered dose of each suspension were measured. The results are reported in Table C1 below.

[0279] Table ExC1

[0280]

[0281] Generally speaking, the prescription dose of an API is achieved through two clicks of an MDI, meaning that the nominal prescription dose used each time is 200 μg.

[0282] Example 1: A suspension of salbutamol sulfate in a mixture of HFO-1234ze(E) and ethanol. Delivery dosage and particle size measurements, wherein the nominal API dose per actuation is 200 μg.

[0283] Salbutamol sulfate (API) was suspended in HFC-1234ze(E) and a mixture of HFC-1234ze(E) and ethanol, in amounts indicated in Table E1 below. Each suspension was formed with approximately 3.8 mg / mL of salbutamol sulfate to provide a nominal dose of approximately 200 μg / puff. Each suspension was filled into FEP-coated canisters, coiled with a 63 pL valve, and tested using commercially available actuators. The fine particle mass (FPM), fine particle fraction (FPF), and delivered dose of each suspension were measured. The results are reported in Table E1 below.

[0284] Table E1

[0285]

[0286] As shown in the test results reported in Table Ex1 above (and... Figures 4-6 As shown in the figure, the applicant has found that the compositions, systems, and methods according to preferred aspects of the invention produce significant but unexpected results and advantages. These unexpected advantages include the ability to provide a composition that forms a stable suspension while providing an APR delivery dose of greater than 150 micrograms per actuation, which is substantially and unexpectedly twice the value achieved in Comparative Example 1 (>2X). Furthermore, the fine particle fraction achieved according to the invention is unexpectedly significantly higher than that achieved in Comparative Example 1. The fine particle dose (FPM) per actuation is also significantly and unexpectedly significantly higher than the value achieved according to Comparative Example 1. The following figures compare the results of Comparative Example 1 and Example 1, illustrating these unexpected advantages.

[0287] Example 2: Mixing of salbutamol sulfate suspension in a mixture of HFO-1234ze(E), ethanol, and oleic acid The delivery dose and particle size of the suspension were measured, with each actuation representing a nominal API dose of 200 μg.

[0288] Salbutamol sulfate (API) was suspended in a mixture of HFC-1234ze(E), ethanol, and oleic acid in amounts indicated in Table E2 below. Each suspension was formed with approximately 3.8 mg / mL of salbutamol sulfate to provide a nominal API dose of approximately 200 μg / puff. Each suspension was filled into FEP-coated canisters, coiled with a 63 pL valve, and tested using a commercially available actuator. The fine particle mass (FPM), fine particle fraction (FPF), and delivered dose (before experiment) of each suspension were measured. The results are shown in Table E2 below.

[0289] Table E2

[0290]

[0291] As can be seen from the test results reported in Table E2 above, the applicant has discovered that the compositions according to the preferred aspects of the present invention not only produce important and unexpected results and advantages related to Example 1 above, but also produce other unexpected and important advantages. Among the other unexpected advantages brought about by the use of oleic acid in the compositions of the present invention, the amount of oleic acid is greater than 0.005% by weight (preferably greater than 0.005% to about 0.001%), and the concentration of ethanol in the composition is greater than 2% to less than about 6%. Under these conditions, the applicant unexpectedly discovered that, for the data of compositions without oleic acid, when the ethanol concentration increased to more than 2%, a deterioration in FPM and API delivery dose occurred. The preferred amounts of oleic acid and ethanol in the preferred embodiment of this example produced an unexpected reversal of this trend and produced unexpectedly high maximum values ​​for FPM and API delivery dose. This unexpected result in Figures 7-9 The data shown includes data from Comparative Example 1, Example 1, and Example 2.

Claims

1. A pharmaceutical composition comprising: a. Fine particles of salbutamol; b. HFO-1234ze(E) greater than 95% by weight and less than about 98% by weight; and c. Ethanol greater than 2% by weight and less than 5% by weight.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises essentially the following: a. The fine particles of the salbutamol; b. The HFO-1234ze(E); as well as c. The ethanol.

3. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition further comprises more than 0.005% by weight to less than 0.015% by weight of oleic acid.

4. The pharmaceutical composition according to claim 1, wherein the fine particles of salbutamol comprise fine particles of salbutamol sulfate.

5. The pharmaceutical composition according to claim 1, wherein the fine particles of salbutamol are substantially composed of fine particles of salbutamol sulfate.

6. The pharmaceutical composition according to claim 1, wherein the fine particles of salbutamol are composed of fine particles of salbutamol sulfate.

7. The pharmaceutical composition according to claim 1, wherein the salbutamol is present in an amount from about 2.5 mg / mL to less than about 4.5 mg / mL.

8. The pharmaceutical composition according to claim 1, wherein the HFO-1234ze(E) is present in an amount greater than 96% by weight to less than about 98% by weight, and the ethanol is present in an amount greater than 2% by weight to less than 4% by weight.

9. A pharmaceutical composition in aerosol form, said pharmaceutical composition comprising: a. Fine particles of salbutamol sulfate; and b. A carrier for the fine particles of said salbutamol sulfate, said carrier comprising: (i) about 94% to less than 99% by weight of HFO-1234ze(E); and (ii) more than 1% to about 6% by weight of ethanol, wherein the amount of said salbutamol sulfate in the aerosol is about more than 150 micrograms to about 300 micrograms.

10. A method for delivering a prescribed dose of salbutamol sulfate, the method comprising: a. Provided in an MDI comprising an actuator and a pharmaceutical composition, said pharmaceutical composition comprising: (1) a carrier comprising greater than about 95% by weight to less than 99% by weight of HFO-1234ze(E); and (ii) greater than 1% by weight to about 5% by weight of ethanol; and (2) fine particles of salbutamol sulfate; and b. Actuate the MDI once to generate a single aerosol spray of the salbutamol sulfate, wherein the single spray contains a prescribed dose of the salbutamol sulfate.

Images