HRP20041210A2 - Method and packaging for pressurized containers - Google Patents

Description

Field of invention

This invention relates to the process and packaging of packages with pressurized containers suitable for relatively long-term storage. More specifically, it refers to packages and packaging processes that use an HFA absorbent material, such as a molecular sieve, to absorb or adsorb propellant gases gradually escaping from a pressurized container, while preventing the propellant gas from penetrating the package. .

Background of the invention

Pressurized containers such as inhalers may need to be sealed in airtight packages to prevent atmospheric moisture from entering them. The use of such leaky packages may cause the accumulation of pressure gas that gradually escapes from the pressurized container and may eventually lead to loosening of the welds on the package. This problem becomes more apparent when traditional chlorofluorocarbon (CFCs) propellants are replaced by hydrofluoroalkane propellants (such as HFA-134a and HFA-227) for environmental reasons.

US patents no. 6,179,118 B1, no. 6,119,853 and no. 6,352,152 approaches this problem by using a flexible package that is "impermeable to moisture and permeable to propellant gas". While this appears to be a good approach to the problem, applicants have considerable difficulty in producing a flexible wrap material that is impermeable to moisture and permeable to the propellant gas so that the resulting package would act similarly to a "true check valve." In all likelihood, the production of such flexible wrapping material is technically more demanding and expensive than it appears from reading the above patents. Therefore, there is a need for a simpler and more understandable way of solving the problem of inflation when packing pressurized containers.

Furthermore, the capability of the packages disclosed in US Pat. Nos. 6,179,118 B1, no. 6,119,853 and no. 6,352,152, to prevent gas build-up in packages, appears to be limited by the permeability of the propellant wrapping material and the rate at which the propellant is released from the container.

Therefore, there is a need to improve a drug product contained in a package that is impermeable, or substantially impermeable, to the release of HFA gas from the package, and can still maintain the closed volume of the sealed package at approximately ambient pressure when leakage of the HFA propellant gas occurs.

The essence of invention

A primary object of the present invention is to provide a novel packaging for pressurized inhalers which will reduce or eliminate the inflation problems normally associated with conventional packaging processes. Another object of the present invention is to provide a simpler method for solving the problem of package inflation than has been provided by previous approaches to this problem. It is a further object of the present invention to provide a novel packaging for pressurized inhalers which will reduce or eliminate leakage of HFA propellant gas from the package normally associated with conventional packaging processes. It is a further object of this invention to provide a method for maintaining a closed volume of a sealed package at approximately ambient pressure, when the package is leaking from a pressurized container containing HFA (hydrofluoroalkane) propellant gas.

The mechanism by which HFA absorbent materials prevent pack inflation is believed to be by trapping the propellant gas that gradually escapes from the pressurized container.

The various features of novelty characterizing this invention are pointed out with particularity in the claims which are appended and form a part of this invention. For a better understanding of this invention, its operational advantages, and the specific goals achieved by its use, the following pictures and descriptions should be provided in which the preferred embodiments of this invention are illustrated and described.

Short description of the pictures

Figure 1 is a diagram summarizing research showing that molecular sieves are an effective HFA adsorbent that captures propellant from air, preventing pack inflation.

Figure 2 shows the rate of moisture absorption on molecular sieves during the first hour of exposure to the atmosphere.

Figure 3 shows the rate of moisture absorption on the same molecular sieves used in Figure 2 during exposure for a period of 12 hours.

Figures 4 and 5 show that the capacity of molecular sieves for the adsorption of pressure gases decreases if the sieves are previously exposed to moisture for different time intervals.

Figure 6 depicts a package with a typical metered dose inhaler (pressurized container) in accordance with the present invention.

An exhaustive description of preferred embodiments of the invention

(1) In the first embodiment, the invention provides a method for maintaining the closed volume of a sealed package under approximately ambient pressure, where the package contains a pressurized container MDI (metered dose inhaler) in which there is a medicine, and an HFA (hydrofluoroalkane) propellant gas selected from the group consisting of HFA 134a and HFA p227, or their mixture; whereby the procedure consists of steps:

(i) placing an effective amount of the HFA adsorbent material, and said pressurized container, in a sealable package;

(ii) sealing the package so that the pressurized container and the adsorbent are in a closed volume within the package at a pressure approximately equal to the ambient;

(iii) adsorption of the leaked HFA propellant gas in the HFA adsorbent material so that the enclosed volume is maintained at approximately ambient pressure.

(2) In another embodiment, the invention provides a procedure in accordance with embodiment (1), whereby the drug is selected from the group consisting of bronchodilators, antihistamines, pulmonary surfactants, antiviral agents, corticosteroids, anti-inflammatory agents, anticholinergics, and antibacterial agents.

(3) In yet another embodiment, the invention provides a method in accordance with embodiment (1) or (2), wherein the pressurized container MDI (metered dose inhaler) further contains one or more excipients selected from the group consisting of surfactants , preservatives, flavoring agents, antioxidants, anti-caking agents and co-solvents.

(4) In yet another embodiment, the invention provides a method in accordance with any of embodiments (1) to (3), wherein the HFA propellant gas is HFA 134a.

(5) In yet another embodiment, the invention provides a method according to any one of embodiments (1) to (3), wherein the HFA propellant gas is HFA p227.

(6) In yet another embodiment, the invention provides a process in accordance with any of embodiments (1) to (5), wherein the HFA adsorbent material has the ability to adsorb HFA thrust gas up to about 25% of the weight of the adsorbent,

(7) In yet another embodiment, the invention provides a method in accordance with any of embodiments (1) to (5), wherein the HFA gas adsorption material has the ability to adsorb HFA pressure gas up to about 20% of the weight of the adsorbent.

(8) In another embodiment, the invention provides a method in accordance with any of embodiments (1) to (7), wherein the HFA adsorption material is a material selected from the group consisting of molecular sieves, active clays, active aluminum oxide, silicon oxide, zeolite, bauxite, and their mixtures.

(9) In another embodiment, the invention provides a procedure in accordance with embodiment (8), wherein the HFA adsorption material is represented by 10 A (Angstrom) molecular sieves.

(10) In another embodiment, the invention provides a procedure in accordance with embodiment (9), whereby the molecular sieves, in an amount of about 4 grams, absorb about 230 ml of HFA p227.

(11) In another embodiment, the invention provides a procedure in accordance with embodiment (9), wherein the molecular sieves, in an amount of about 4 grams, absorb about 230 ml of HFA 134a.

(12) In yet another embodiment, the invention provides a method in accordance with any of embodiments (1) to (11), wherein the package is impermeable to HFA 134a.

(13) In yet another embodiment, the invention provides a method according to any one of embodiments (1) to (12), wherein the package is impermeable to HFA p227.

(14) In yet another embodiment, the invention provides a method according to any one of embodiments (1) to (12), wherein the packet is passed for HFA p227.

(15) In yet another embodiment, the invention provides a method in accordance with embodiment (14), wherein the package has a permeability for HFA p227 that is less than or equal to about 0.25 cc of HFA p227 per square meter of the package per day at a pressure of about 1 at least at room temperature.

(16) In yet another embodiment, the invention provides a method in accordance with embodiment (14), wherein the package has a permeability for HFA p227 that is less than or equal to about 0.15 cc of HFA p227 per square meter of the package per day at a pressure of about 1 at least at room temperature.

(17) In yet another embodiment, the invention provides a method in accordance with embodiment (14), wherein the package has a permeability for HFA p227 that is less than or equal to about 0.10 cc of HFA p227 per square meter of the package per day at a pressure of about 1 at least at room temperature.

(18) In yet another embodiment, the invention provides a method in accordance with embodiment (14), wherein the package has a permeability for HFA p227 that is less than or equal to about 0.05 cc of HFA p227 per square meter of the package per day at a pressure of about 1 at least at room temperature.

(19) In yet another embodiment, the invention provides a method according to any one of embodiments (1) to (11) or (14), wherein the packet is passed for HFA 134a.

(20) In yet another embodiment, the invention provides a method in accordance with embodiment (19), wherein the package has a permeability for HFA 134a that is less than or equal to about 4.1 cc of HFA 134a per square meter of the package per day at a pressure of about 1 at least at room temperature.

(21) In yet another embodiment, the invention provides a process in accordance with embodiment (19), wherein the package has a permeability for HFA 134a that is less than or equal to about 3.5 cc of HFA 134a per square meter of the package per day at a pressure of about 1 at least at room temperature.

(22) In yet another embodiment, the invention provides a method in accordance with embodiment (19), wherein the package has a permeability for HFA 134a that is less than or equal to about 2.5 cc of HFA 134a per square meter of the package per day at a pressure of about 1 at least at room temperature.

(23) In yet another embodiment, the invention provides a method in accordance with embodiment (19), wherein the package has a permeability for HFA 134a that is less than or equal to about 1.5 cc of HFA 134a per square meter of the package per day at a pressure of about 1 at least at room temperature.

(24) In yet another embodiment, the invention provides a method in accordance with embodiment (19), wherein the package has a permeability for HFA 134a that is less than or equal to about 1.0 cc of HFA 134a per square meter of the package per day at a pressure of about 1 at least at room temperature.

(25) In yet another embodiment, the invention provides a method in accordance with embodiment (19), wherein the package has a permeability for HFA 134a that is less than or equal to about 0.5 cc of HFA 134a per square meter of the package per day at a pressure of about 1 at least at room temperature.

(26) In another embodiment, the invention provides a procedure in accordance with any of embodiments (1) to (25), wherein the package is made of metal, glass, or plastic, and selected from the group consisting of bottles, bags , a drum-shaped box, and an irregularly shaped container.

(27) In yet another embodiment, the invention provides a method according to any one of embodiments (1) to (26), wherein the package is made of plastic.

(28) In yet another embodiment, the invention provides a method in accordance with embodiment (27), wherein the plastic is a flexible laminate having a barrier layer that gives said package permeability to HFA 134a and/or HFA p227.

(29) In another embodiment, the invention provides a method in accordance with embodiment (27), wherein the plastic is a flexible laminate having a barrier layer that renders said package impervious to HFA 134a and/or HFA p227.

(30) In another embodiment, the invention brings a process in accordance with embodiment (28) or (29), wherein said flexible laminate has three layers: polyester/aluminum/polyethylene, where the aluminum layer is located between the layers of polyester and polyethylene.

(31) In yet another embodiment, the invention provides a procedure in accordance with embodiment (28) or (29), wherein the said barrier layer is made of aluminum foil.

(32) In yet another embodiment, the invention provides a method according to any of embodiments (1) to (31), wherein the sealed package is hermetically sealed by means of heat sealing, gluing, welding, soldering, mechanical fasteners or clips, or compression .

(33) In the following embodiment, the invention brings the use of HFA adsorbent to maintain the pressure of a closed volume inside a sealed package under approximately ambient pressure, wherein the sealed package contains:

(i) a pressurized MDI (metered dose inhaler) container containing the drug, and an HFA (hydrofluoroalkane) propellant gas selected from the group consisting of HFA 134a and HFA p227, or a mixture thereof;

(ii) an effective amount of HFA adsorbent material;

wherein the MDI pressurized container and the HFA adsorbent material are contained within the closed volume of the sealed package.

(34) In another embodiment, the invention provides use in accordance with embodiment (33), wherein the drug is selected from the group consisting of bronchodilators, antihistamines, pulmonary surfactants, antiviral agents, corticosteroids, anti-inflammatory agents, anticholinergics, and antibiotics.

(35) In another embodiment, the invention provides use in accordance with embodiment (33) or (34), wherein the MDI pressurized container (metered dose inhaler) further contains one or more excipients selected from the group consisting of surfactants, preservatives , flavoring agents, antioxidants, anti-caking agents and co-solvents.

(36) In yet another embodiment, the invention provides a use according to any one of embodiments (33) to (35), wherein the HFA propellant is HFA 134a.

(37) In yet another embodiment, the invention provides a use according to any one of embodiments (33) to (35), wherein the HFA propellant gas is HFA p227.

(38) In yet another embodiment, the invention provides a use in accordance with any of embodiments (33) to (37), wherein the HFA adsorbent material has the ability to adsorb HFA thrust gas up to about 25% of the weight of the adsorbent.

(39) In yet another embodiment, the invention brings use in accordance with any of embodiments (33) to (37), wherein the HFA gas adsorption material has the ability to adsorb HFA thrust gas up to about 20% of the weight of the adsorbent.

(40) In another embodiment, the invention brings use in accordance with any of embodiments (33) to (39), wherein the HFA adsorption material is a material selected from the group consisting of molecular sieves, active clays, active aluminum oxide, silicon oxide, zeolite, bauxite, and their mixtures.

(41) In another embodiment, the invention provides use in accordance with embodiment (40), wherein the HFA adsorption material is represented by 10 A (Angstrom) molecular sieves.

(42) In yet another embodiment, the invention brings use in accordance with embodiment (41), whereby the molecular sieves, in an amount of about 4 grams, absorb about 230 ml of HFA p227.

(43) In yet another embodiment, the invention brings use in accordance with embodiment (41), whereby the molecular sieves, in an amount of about 4 grams, absorb about 230 ml of HFA 134a,

(44) In yet another embodiment, the invention provides a use in accordance with any of embodiments (33) to (43), wherein the package is impermeable to HFA 134a.

(45) In yet another embodiment, the invention provides a use according to any one of embodiments (33) to (42), wherein the package is impermeable to HFA p227.

(46) In yet another embodiment, the invention provides a use according to any one of embodiments (33) to (42), wherein the packet is passed for HFA p227.

(47) In another embodiment, the invention provides a use in accordance with embodiment (46), wherein the package has a permeability for HFA p227 that is less than or equal to about 0.25 cc of HFA p227 per square meter of the package per day at a pressure of about 1 at least at room temperature.

(48) In yet another embodiment, the invention provides a use in accordance with embodiment (46), wherein the package has a permeability for HFA p227 that is less than or equal to about 0.15 cc of HFA p227 per square meter of the package per day at a pressure of about 1 at least at room temperature.

(49) In another embodiment, the invention provides use in accordance with embodiment (46), wherein the package has a permeability for HFA p227 that is less than or equal to about 0.10 cc of HFA p227 per square meter of the package per day at a pressure of about 1 bar and at approximately room temperature.

(50) In yet another embodiment, the invention provides a use in accordance with embodiment (46), wherein the package has a permeability for HFA p227 that is less than or equal to about 0.05 cc of HFA p227 per square meter of the package per day at a pressure of about 1 at least at room temperature.

(51) In yet another embodiment, the invention provides a use in accordance with any one of embodiments (33) to (43), wherein the packet is passed for HFA 134a.

(52) In yet another embodiment, the invention provides a use in accordance with embodiment (51), wherein the package has a permeability for HFA 134a that is less than or equal to about 4.1 cc of HFA 134a per square meter of the package per day at a pressure of about 1 at least at room temperature.

(53) In yet another embodiment, the invention provides a use in accordance with embodiment (51), wherein the package has a permeability for HFA 134a that is less than or equal to about 3.5 cc of HFA 134a per square meter of the package per day at a pressure of about 1 at least at room temperature.

(54) In yet another embodiment, the invention provides a use in accordance with embodiment (51), wherein the package has a permeability for HFA 134a that is less than or equal to about 2.5 cc of HFA 134a per square meter of the package per day at a pressure of about 1 at least at room temperature.

(55) In yet another embodiment, the invention provides a use in accordance with embodiment (51), wherein the package has a permeability for HFA 134a that is less than or equal to about 1.5 cc of HFA 134a per square meter of the package per day at a pressure of about 1 at least at room temperature.

(56) In yet another embodiment, the invention provides a use in accordance with embodiment (51), wherein the package has a permeability for HFA 134a that is less than or equal to about 1.0 cc of HFA 134a per square meter of package per day at a pressure of about 1 at least at room temperature.

(57) In yet another embodiment, the invention provides a use in accordance with embodiment (51), wherein the package has a permeability for HFA 134a that is less than or equal to about 0.5 cc of HFA 134a per square meter of the package per day at a pressure of about 1 at least at room temperature.

(58) In another embodiment, the invention provides use in accordance with any of embodiments (33) to (57), wherein the package is made of metal, glass, or plastic, and selected from the group consisting of bottles, bags , a drum-shaped box, and an irregularly shaped container.

(59) In another embodiment, the invention provides a use in accordance with embodiment (58), wherein the package is made of plastic.

(60) In yet another embodiment, the invention brings use in accordance with embodiment (59), wherein the plastic is a flexible laminate having a barrier layer that renders said package impervious to HFA 134a and/or HFA p227.

(61) In yet another embodiment, the invention provides a use in accordance with embodiment (59) or (60), wherein the plastic is a flexible laminate having a barrier layer that gives said package permeability to HFA 134a and/or HFA p227.

(62) In another embodiment, the invention is used in accordance with embodiment (60) or (61), wherein said flexible laminate has three layers: polyester/aluminum/polyethylene, where the aluminum layer is located between the layers of polyester and polyethylene.

(63) In yet another embodiment, the invention provides use in accordance with embodiment (60) or (61), wherein said barrier layer is made of aluminum foil.

(64) In yet another embodiment, the invention provides a use in accordance with any of embodiments (33) to (63), wherein the sealed package is hermetically sealed by heat sealing, gluing, welding, soldering, mechanical fasteners or clips, or compression ,

(65) In the following embodiment, the invention provides a pharmaceutical product consisting of:

(i) a pressurized MDI (metered dose inhaler) container containing the drug, and HFA (hydrofluoroalkane) propellant gas selected from the group consisting of HFA 134a and HFA p227, or their mixture;

(ii) effective amounts of HFA adsorbent material; and

(iii) a sealed package with a closed volume inside which there are a pressurized container and HFA adsorption material,

wherein the sealed package is impermeable to the HFA propellant gas and the pressure within the sealed volume is approximately equal to the ambient pressure;

and

wherein the HFA adsorbent material is capable of adsorbing the HFA propellant gas so that the pressure within said closed volume is maintained constant, when the HFA propellant gas escapes from the pressurized container.

(66) In another embodiment, the invention provides a pharmaceutical product in accordance with embodiment (65), wherein the drug is selected from the group consisting of bronchodilators, antihistamines, pulmonary surfactants, antiviral agents, corticosteroids, anti-inflammatory agents, anticholinergics, and antibiotics .

(67) In another embodiment, the invention provides a pharmaceutical product according to embodiment (65) or (66), wherein the MDI pressurized container (metered dose inhaler) further contains one or more excipients selected from the group consisting of surfactants, preservatives, flavoring agents, antioxidants, anti-caking agents and co-solvents.

(68) In yet another embodiment, the invention provides a pharmaceutical product according to any one of embodiments (65) to (67), wherein the HFA propellant gas is HFA 134a.

(69) In yet another embodiment, the invention provides a pharmaceutical product according to any one of embodiments (65) to (67), wherein the HFA propellant gas is HFA p227.

(70) In yet another embodiment, the invention provides a pharmaceutical product according to any one of embodiments (65) to (69), wherein the HFA adsorbent material has the ability to adsorb HFA thrust gas up to about 25% by weight of the adsorbent.

(71) In yet another embodiment, the invention provides a pharmaceutical product according to any of embodiments (65) to (69), wherein the HFA gas adsorption material has the ability to adsorb HFA thrust gas up to about 20% of the weight of the adsorbent.

(72) In another embodiment, the invention provides a pharmaceutical product according to any one of embodiments (65) to (71), wherein the HFA adsorption material is a material selected from the group consisting of molecular sieves, active clays, active aluminum oxide , silicon oxide, zeolite, bauxite, and their mixtures.

(73) In another embodiment, the invention provides a pharmaceutical product in accordance with embodiment (72), wherein the HFA adsorption material is represented by 10 A (Angstrom) molecular sieves.

(74) In yet another embodiment, the invention provides a pharmaceutical product in accordance with embodiment (73), whereby the molecular sieves, in an amount of about 4 grams, absorb about 230 ml of HFA p227.

(75) In yet another embodiment, the invention provides a pharmaceutical product in accordance with embodiment (73), whereby the molecular sieves, in an amount of about 4 grams, absorb about 230 ml of HFA 134a.

(76) In yet another embodiment, the invention provides a pharmaceutical product according to any one of embodiments (65) to (75), wherein the package is impermeable to HFA 134a.

(77) In yet another embodiment, the invention provides a pharmaceutical product according to any one of embodiments (65) to (75), wherein the package is impermeable to HFA p227.

(78) In another embodiment, the invention provides a pharmaceutical product according to any one of embodiments (65) to (77), wherein the package is made of metal, glass, or plastic, and is selected from the group consisting of bottles, bags, drum-shaped boxes, and irregularly shaped containers.

(79) In another embodiment, the invention provides a pharmaceutical product in accordance with embodiment (71), wherein the package is made of plastic.

(80) In yet another embodiment, the invention provides a pharmaceutical product according to embodiment (79), wherein the plastic is a flexible laminate having a barrier layer that renders said package impervious to HFA 134a and/or HFA p227.

(81) In another embodiment, the invention provides a pharmaceutical product according to embodiment (80), wherein said flexible laminate has three layers: polyester/aluminum/polyethylene, where the aluminum layer is located between the layers of polyester and polyethylene.

(82) In yet another embodiment, the invention provides a pharmaceutical product in accordance with embodiment (80), wherein said barrier layer is made of aluminum foil.

(83) In yet another embodiment, the invention provides a pharmaceutical product according to any one of embodiments (65) to (82), wherein the sealed package is hermetically sealed by means of heat sealing, gluing, welding, soldering, mechanical fasteners or fasteners, or compression.

(84) Pharmaceutical products containing:

(i) a pressurized MDI (metered dose inhaler) container containing the drug, and an HFA (hydrofluoroalkane) propellant gas selected from the group consisting of HFA 134a and HFA p227, or a mixture thereof;

(ii) an effective amount of HFA adsorbent material; and

(iii) a sealed package with a closed volume containing a pressurized container and HFA adsorption material,

wherein the sealed package is impermeable to the HFA propellant gas and the pressure within the sealed volume is approximately equal to the ambient pressure;

wherein the HFA adsorbent material is capable of adsorbing the HFA propellant gas so that the pressure within said

keeps the closed volume constant, when the HFA pressure gas leaks out of the pressurized container; and

wherein the package has a permeability to HFA p227 that is less than or equal to about 0.25 cc of HFA p227 per square meter of package per day at a pressure of about 1 bar and at about room temperature, or has a permeability to HFA 134a that is less than or equal to about 4.1 cc of HFA 134a per square meter of package per day at a pressure of about 1 bar and at about room temperature.

(85) The pharmaceutical product according to embodiment (84), wherein the package has a permeability to HFA p227 that is less than or equal to about 0.15 cc of HFA p227 per square meter of package per day at a pressure of about 1 bar and at about room temperature .

(86) The pharmaceutical product according to embodiment (84), wherein the package has a permeability to HFA p227 that is less than or equal to about 0.10 cc of HFA p227 per square meter of package per day at a pressure of about 1 bar and at about room temperature .

(87) The pharmaceutical product according to embodiment (84), wherein the package has a permeability to HFA p227 that is less than or equal to about 0.05 cc of HFA p227 per square meter of package per day at a pressure of about 1 bar and at about room temperature .

(88) The pharmaceutical product according to embodiment (84), wherein the package has a permeability for HFA 134a that is less than or equal to about 3.5 cc of HFA 134a per square meter of package per day at a pressure of about 1 bar and at about room temperature .

(89) The pharmaceutical product according to embodiment (84), wherein the package has a permeability for HFA 134a that is less than or equal to about 2.5 cc of HFA 134a per square meter of package per day at a pressure of about 1 bar and at about room temperature .

(90) The pharmaceutical product according to embodiment (84), wherein the package has a permeability for HFA 134a that is less than or equal to about 1.5 cc of HFA 134a per square meter of package per day at a pressure of about 1 bar and at about room temperature .

(91) The pharmaceutical product according to embodiment (84), wherein the package has a permeability for HFA 134a that is less than or equal to about 1.0 cc of HFA 134a per square meter of package per day at a pressure of about 1 bar and at about room temperature .

(92) The pharmaceutical product according to embodiment (84), wherein the package has a permeability for HFA 134a that is less than or equal to about 0.5 cc of HFA 134a per square meter of package per day at a pressure of about 1 bar and at about room temperature .

(93) In the next embodiment, the invention provides a pharmaceutical product according to any one of embodiments (84) to (92), wherein the drug is selected from the group consisting of bronchodilators, antihistamines, pulmonary surfactants, antiviral agents, corticosteroids, anti-inflammatory agents, anticholinergics, and antibiotics.

(94) In yet another embodiment, the invention provides a pharmaceutical product according to any one of embodiments (84) to (93), wherein the MDI (metered dose inhaler) pressurized container further contains one or more excipients selected from the group consisting of surface active substances, preservatives, flavoring substances, antioxidants, anti-caking agents and co-solvents.

(95) In yet another embodiment, the invention provides a pharmaceutical product according to any one of embodiments (84) to (94), wherein the HFA propellant gas is HFA 134a.

(96) In yet another embodiment, the invention provides a pharmaceutical product according to any one of embodiments (84) to (94), wherein the HFA propellant gas is HFA p227.

(97) In yet another embodiment, the invention provides a pharmaceutical product according to any one of embodiments (84) to (96), wherein the HFA adsorbent material has the ability to adsorb HFA thrust gas up to about 25% by weight of the adsorbent.

(98) In yet another embodiment, the invention provides a pharmaceutical product according to any one of embodiments (84) to (96), wherein the HFA gas adsorption material has the ability to adsorb HFA thrust gas up to about 20% of the weight of the adsorbent.

(99) In another embodiment, the invention provides a pharmaceutical product according to any one of embodiments (84) to (98), wherein the HFA adsorption material is a material selected from the group consisting of molecular sieves, active clays, active aluminum oxide , silicon oxide, zeolite, bauxite, and their mixtures.

(100) In another embodiment, the invention provides a pharmaceutical product in accordance with embodiment (99), wherein the HFA adsorption material is represented by 10 A (Angstrom) molecular sieves.

(101) In yet another embodiment, the invention provides a pharmaceutical product in accordance with embodiment (100), whereby the molecular sieves, in an amount of about 4 grams, absorb about 230 ml of HFA p227.

(102) In yet another embodiment, the invention provides a pharmaceutical product in accordance with embodiment (100), whereby the molecular sieves, in an amount of about 4 grams, absorb about 230 ml of HFA 134a.

(103) In another embodiment, the invention provides a pharmaceutical product according to any one of embodiments (84) to (102), wherein the package is made of metal, glass, or plastic, and is selected from the group consisting of bottles, bags, drum-shaped boxes, and irregularly shaped containers.

(104) In another embodiment, the invention provides a pharmaceutical product in accordance with embodiment (103), wherein the package is made of plastic.

(105) In yet another embodiment, the invention provides a pharmaceutical product according to embodiment (104), wherein the plastic is a flexible laminate having a barrier layer that gives said package permeability to HFA 134a and/or HFA p227.

(106) In another embodiment, the invention provides a pharmaceutical product in accordance with embodiment (105), wherein said flexible laminate has three layers: polyester / aluminum / polyethylene, where the aluminum layer is located between the layers of polyester and polyethylene.

(107) In yet another embodiment, the invention provides a pharmaceutical product in accordance with embodiment (105), wherein said barrier layer is made of aluminum foil.

(108) In yet another embodiment, the invention provides a pharmaceutical product according to any one of embodiments (84) to (107), wherein the sealed package is hermetically sealed by means of heat sealing, gluing, welding, soldering, mechanical fasteners or fasteners, or compression.

(109) In yet another embodiment, the invention provides a flexible laminate according to any of embodiments (30), (62), (81), and (106) consisting of 12 micron polyester/9 micron aluminum foil/50 micron polyethylene.

It is recognized that certain features of the invention, which, for the sake of clarity, are described in the context of separate embodiments, may also be realized in combination in a single embodiment. Also, the various features of the invention which, for the sake of brevity, are described in the context of a single embodiment, may be embodied separately or in any suitable sub-combination.

Ability of HFA adsorbent to remove pusher gases

It has been discovered that HFA adsorption materials, especially molecular sieves, possess the ability to remove (by trapping) pusher gases from the immediate environment. The present invention takes advantage of this property of the HFA adsorbent material by enclosing it in an impermeable, or substantially impermeable, flexible package as a means of preventing package inflation due to released propellant gas. By enclosing one or more HFA adsorbent materials in the package to adsorb or absorb the released propellant gas, applicants can make the flexible wrapping material as impermeable as possible to prevent moisture ingress without having to worry about the released propellant gas inflating package and cause the welds on the flexible package to crack. In order to determine the appropriate type and amount of HFA adsorbent material to be used in each individual pressurized inhaler package containing a specific propellant gas, applicants performed the following measurements and determined that approximately 4 grams of 10 Angstrom molecular sieve packets can remove (adsorb ) approximately 230 ml of HFA-227 propellant gas.

In order to determine the absorption capacity of the sieve, two procedures are used. The initial measurement procedure uses sealed packages containing the active product to provide an approximation of the amount of propellant gas that would be absorbed. The precision measurement procedure builds on the results obtained by the initial measurement procedure but uses tanks filled only with propellant gas in order to eliminate any effect of the active compound (ie drug).

For the initial measurement procedure, a number of sample packages (a flexible package enclosing a pressurized inhaler containing HFA-227 propellant and the molecular sieve to be tested) were taken and the integrity of the welds was verified by testing with a Qualitek outgassing tester. Packets are directed with the pressurized inhaler valve upwards. With as little disturbance as possible, the direction of the package is changed (with the valve downwards) and a previously determined number of aerosol shots are performed and the time required for each package to subside is recorded. The reason for these precautions is to minimize the release of the active product with the pressure gas, which can envelop the sieves and reduce their absorption capacity. The presence of the active product would indicate that twisting did not prevent release of the active product and as a consequence it could affect the rate of absorption. The results of the initial measurement are as follows:

All packs that received up to 15 shots returned to their original size within 10 minutes, while packs that received 20 shots showed little shrinkage after 15 minutes. Examination of the used sieves showed evidence of product deposition on the inside of the bag and on the outside of the bag with the adsorbent, although nothing is visible on the surface of the adsorbent itself. As such this test is considered a good measure of adsorbent capacity before undertaking more precise procedures.

In the process of precise measurement, further steps follow:

1. A number of pressurized inhalers (aerosol canisters) filled with only HFA-227 propellant gas were obtained. They are numbered and their weights are recorded.

2. A number of open-ended flexible packages were procured. They are also numbered.

3. Each aerosol container is placed in the activation device and inserted into the flexible package.

4. Transfer the previously determined number of molecular sieves from the unused polyethylene bag to a smaller bag with a zipper. Using tweezers to avoid moisture transfer, the sieves are weighed and inserted into each individual package.

5. Each of the packs, now containing the aerosol container and molecular sieves, is immediately heat sealed using an AstraPak Heatsealer machine that is tuned to produce effective seals with this special pack material. This step is repeated for all packages.

6. The first five packages remain sealed. This is to assess the effect of moisture build-up from the actuation device and/or air in the package, which can serve as a baseline for all other measurements.

7. The remaining packages are divided into groups of five packages. A predetermined number of shots are fired at a group of tanks. The maximum number of shots is determined based on the information obtained from the initial measurement procedure. Groups with more than 10 shots are allowed some time to subside before proceeding with the next shot. All package groups are stored for at least 24 hours to allow maximum absorption of propellant gas,

8. Leakage was then tested using a Qualitek gas leak tester to ensure that all packages were properly sealed and that the data obtained was relevant. Results of packages that did not pass the gas leak test were discarded.

9. Each package is opened in turn and the sieve and container are weighed again. First, the sieve is weighed to avoid an increase in weight due to the absorption of atmospheric moisture.

10. The weight loss from each tank and the increase in sieve weight were obtained and the mean value was calculated for each group. The data is then plotted graphically to show the rate of increase in sieve weight and the number of shots (and thus the volume of gas) required to achieve the maximum level of absorption. Similarly, the mean tank weight loss data is plotted on a plot showing the equivalent pressure gas transfer from the tank to the screens until final screen absorption is reached (see Figure 1).

As shown in Figure 1, a comparison of molecular sieve weight gain versus gas volume indicates a steady increase in weight up to about 25 shots (equal to 230 ml) of absorbed propellant gas. This corresponds to a loss in container weight while the weight of the screen remains constant. Thus, it is concluded that about 4 grams of a 10 Angstrom molecular sieve bag can remove (adsorb) approximately 230 ml of HFA-227 propellant gas.

Of course, the capacity of the HFA adsorbent material to absorb the propellant gas may vary under actual production line conditions because the HFA adsorbent material may be pre-exposed to the atmosphere and absorb atmospheric moisture. Moisture absorption limits the ultimate capacity of the HFA adsorbent material to absorb propellant gases. Therefore, this should be taken into account when putting the present invention into practice. In the specific embodiment disclosed herein, applicants first determined the rate at which the HFA adsorbent material absorbed atmospheric moisture under conditions similar to those of an actual production line (see Figures 2 and 3) and then examined the effect of the duration of atmospheric exposure on the final propellant gas adsorption capacity under typical production conditions (see Figures 4 and 5). The data from this research is used to determine the allowable time for the normal production process, always ensuring that the original target amount of propellant gas can be adsorbed.

As shown in Figures 2 and 3, moisture absorption during the first hour of exposure can reach 20% of maximum moisture absorption at 20cC/45% RH (relative humidity) and 34% at 25°C/60% RH. The applicants of this application also examined the difference in moisture absorption between screens located at the top and bottom of the tank and found that molecular sieves exposed directly to the atmosphere absorb moisture much faster than those protected by being at the bottom of the tank. This supports the view that coiled screens will retain their effectiveness for longer. This data will help determine appropriate procedures for handling molecular sieves in a production environment.

In Figures 4 and 5, the molecular sieves are exposed to production conditions for a prescribed period of time and are immediately packaged using the Astropack heat sealing device. The resulting packs are left for 10 minutes to allow the seals to cool and then the aerosols (charged with propellant gas only) are activated 5 times to fill the packs. The packages are left for the next 10 minutes to allow the adsorption of the pressure gas. The activation process is repeated until each sieve reaches its maximum adsorption capacity. At the end of the 24-hour period (the period that ensures maximum adsorption of the pressure gas), each package is opened and the sieves are immediately weighed. Figure 4 shows that the amount (in grams) of propellant gas adsorbed by 4 grams of molecular sieves decreases after exposure to moisture for the various time periods indicated. Figure 5 shows the percentage of propellant gas adsorption per gram of molecular sieves over the same time periods as in Figure 4. The goal in this particular case is to adsorb 100 ml of HFA-227 propellant gas (equivalent to 0.76 g) using a bag containing 4 grams of molecular sieves. . The data shown in Figure 4 and 5 indicate that this goal can be achieved even if the screens are exposed to normal atmospheric moisture on the production line for 30 minutes.

The results of the above research show that the inclusion of HFA adsorbent within an impermeable, or significantly impermeable, package is a simple, practical and effective solution to the problem of inflating packages for pressurized containers. In particular, molecular sieves are a very effective HFA adsorbent material against package inflation when used in the practice of this invention.

While there are various types of HFA adsorbent material available and their performance against any given propellant may vary significantly, it is understood that those of ordinary skill in the art can readily adopt some conventional test procedures, such as the investigations described above, to determine the type and the amount of HFA adsorbent material that is effective in reducing the inflation of the package caused in particular by the leakage of pressure gas from the pressurized container enclosed in the package.

Propellant gases

Propellant gases for use in the present invention mean pharmacologically inert liquids with a boiling point of about room temperature (25°C) to about -25°C which individually or in combination achieve a high vapor pressure at room temperature. Upon activation of the MDI system, the high pressure of the propellant gas vapor in the MDI pushes a metered amount of drug out through the metering valve while the propellant gas vaporizes the dispersed drug particles very quickly. The propellants used in this invention are more preferably hydrofluorocarbons or hydrofluoroalkanes such as HFA-134a and HFA-227.

Medicines

The term "drug" as used herein is intended to include currently available pharmaceutically active drugs that are used therapeutically and further to include future developed therapeutically effective drugs that can be administered by the intrapulmonary route. The drugs can be selected from, for example, analgesics, eg codeine, dihydromorphine, ergotamine, fentanyl or morphine, angina preparations, eg diltiazem; antiallergic drugs, eg cromoglicate, ketotifen or nedocromil; anti-infectives, eg, cephalosporins, penicillins, streptomycin, sulfonamides, tetracyclines, petnamidine, and neuroaminidase inhibitors, such as zanamivir (Relenza®) available from GlaxoSmithkline; and Ribavirin (Virazole®) manufactured by ICN Pharmaceuticals, Inc.; antihistamines, eg mnetapifilene; antitussives, eg noscapine; beta-adrenergics including bronchodilators such as salbutamol, salmeterol, ephedrine, adrenaline, fenoterol, forinoterol, isoprenaline, phenylephrine, phenylpropanolamine, reproterol, rimiterol, terbutaline, isoetarine, tulobuterol, orciprenaline, or (-)4-amino-3,5 -dichloro-alpha-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol, epinephrine (Primatene), formoterol (Foradil), isoproterenol (Isuprel), isoetarin (Bronkosol), metaproterenol (Alupent, Metaprel), albuterol (Maxair), salmeterol (Severent), combination salmeterol + fluticasone (Advair Diskus), and combination albuterol + atrovent (Combivent); sodium channel blockers such as amiloride, anticholinergics eg ipratropium, atropine or oxotropium; hormones, eg cortisone, hydrocordisone or prednisolone; and therapeutic proteins and peptides, eg insulin or glucagon; Anti-inflammatory drugs used in the treatment of respiratory diseases include steroids such as NASACORT AQ® (triamquinolone acetonide), AZMACORT AQ® (triamquinolone acetonide) flunizolid, fluticasone, budesonide, triamquinolone acetonide, beclomethasone (Vanceril, Beclovent), budesonide ( Pulmicort) dexamethasone, flunizolid (Aerobid), fluticasone (Flovent), combination salmeterol + fluticasone (Advair Diskus), and triamquinolone (Azmacort), and inhibitors that release mediators such as Intal® (cromolyn sodium), and nedocromil sodium (Tilade) ; leukotriene (LT) inhibitors, vasoactive intestinal peptides (VIP), tachykinin antagonists, bradykinin antagonists, endothelin antagonists, heparin furosemide, anti-adhesion molecules, cytokine modulators, biologically active endonucleases, recombinant human (rh) DNase compounds, alpha-antitrypsin and disodium cromoglycate (DSCG); and pulmonary surfactants such as lipid-containing compositions as described in TONGE et al., WO 99/09955; pulmonary surfactants as described in Devendra et al., Respir Res 2002, 3:19; Infasurf® available from ONY; Curosurf® available from Dey Laboratories; Exosurf® by Glaxo Wellcome; Survanta available from Abbot; Surfaxin® pulmonary surfactant available from Discovery Laboratories.

This invention is intended to cover free acids, free bases, salts, amines and various forms of hydrates including forms of semihydrates of such drugs and is particularly directed towards pharmaceutically acceptable forms of such drugs which are formulated in combination with pharmaceutically acceptable excipient materials generally known to persons skilled in the art. preferably without additives such as preservatives.

The preferred form of the drug does not include additional components such as preservatives that have a significant effect on the overall form. Thus, preferred forms consist essentially of a pharmaceutically active drug and a pharmaceutically acceptable carrier (eg, water and/or ethanol). However, as an excipient-free liquid drug, the formulation may consist essentially of a drug having a low enough viscosity that it can be aerosolized using the dispenser of the present invention.

Drug forms

Drug forms for use in the present invention may be free or substantially free of excipients, e.g. surfactants and co-solvents, etc. Such drug forms have the advantage of being predominantly tasteless and odorless, less irritating and less toxic than forms which contain an excipient. Thus, the preferred form of the drug essentially contains the drug, or its physiologically acceptable salt or solvate, optionally in combination with one or more pharmacologically active agents, and the propellant gas hydrofluorocarbon.

Optionally, the aerosol forms according to the present invention may further contain one or more co-solvents. A polar co-solvent such as C2-6 aliphatic alcohols and polyols, e.g. glycerol, ethanol, isopropanol and propylene glycol, more preferably ethanol, may be included in the dosage form in the desired amount, either as an excipient alone or in addition to other excipients, such as surfactants. Suitably, the dosage form may contain 0.01 to 5% w/w based on the propellant as a polar co-solvent, eg ethanol, more suitably 0.1 to 5% w/w, eg about 0.1 to 1% w/w .

Optionally, the aerosol forms according to the present invention may further contain one or more surfactants. Surfactants must be physiologically acceptable when administered by inhalation. Included in this category are surfactants such as oleic acid, sorbitan trioleate, sorbitan mono-oleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan mono-oleate, natural lecithin, oleyl polyoxyethylene (2) ether , stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and oxypropylene, synthetic lecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl mono-oleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol , stearyl alcohol, polyethylene glycol 400, cetyl pyridinium chloride, benzalkonium chloride, olive oil, glyceryl monolaurate, corn oil, cottonseed oil and sunflower seed oil. Preferred surfactants are lecithin, oleic acid and sorbitan trioleate. It is preferable that the amount of surfactants applied is in the range of 0.0001% to 50% w/w in relative proportion to the drug, especially in the proportion of 0.05 to 5% w/w.

Optionally, the aerosol forms according to the present invention may further contain one or more stabilizers. The stabilizer is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine, threonine, isovaline, phenylalanine, tyrosine, serine, histidine, tryptophan, proline, hydroxyproline, arginine, ornithine, asparagine, citrulline, aspartic acid, cysteine, glutamic acid, glutamine, lysine, hydroxylysine, N-acetyl-1-cysteine, phenylalanine, trans-4-hydroxy-1-proline, tyrosine, L-aspartyl-1-phenylalanine methyl ester and mixtures of any of the above compounds.

Optionally, the aerosol forms according to the present invention may further contain one or more antioxidants. The antioxidant can be selected from the group consisting of tocopherol, deteroxime mesylates, methyl paraben, ethyl paraben and ascorbic acid and their mixtures. The preferred antioxidant is tocopherol.

Package

In accordance with one embodiment of the present invention, shown in Figure 6, the pharmaceutical product has an impermeable, or substantially impermeable, flexible package 10, in which a pressurized metered dose container 20, an inhalation device 30 and a molecular sieve 40 are enclosed in a bag 50, sealed in closed volume 60.

The flexible package is conventional and its manufacture is known to those skilled in the art. Generally, the package is constructed from smooth laminates that are folded or otherwise shaped according to packaging equipment technology by sealing and cutting. In this embodiment, the package is constructed from smooth coils of flexible material that is circularly bent into an oblong sleeve, and the sealing 14 is made by heating (welding) the edges of the sleeve to each other. Transverse seals 12 are made using a flat heating pad that compresses the laminate sleeve before and after the contents of the package (ie, inhaler and adsorbent bag). It also cuts the continuous casing into individual packages. As a result, there is a long continuous seal 14 down the middle of the package and transverse seals 12 at both ends thereof.

Other package types may include more or fewer seals according to the desired shape of the container, which may be flat or folded seals, and may include triangular gussets. Seals can be made by heating (welding) or using pressure-sensitive materials. In a further embodiment, the flexible laminates can be formed into pads or bags that contain the product using heat, pressure and/or vacuum and which are then sealed by heating.

Although flexible packages are preferred, other types of envelopes or containers may be suitable, either flexible or inflexible, provided that the chosen envelope is impermeable, or substantially impermeable, to moisture penetration. In general, when the package or envelope is impermeable, or substantially impermeable, to moisture, then it is also impermeable, or substantially impermeable, to the propellant gas gradually escaping from the closed pressurized container. This can gradually increase the pressure inside the package or envelope, which is undesirable. In this context, "substantially impermeable" to propellant gas means that the level of propellant gas in the enclosed volume of the package or envelope will increase unless certain measures are taken to reduce it, such as the incorporation of HFA adsorbent material. In other words, the pressure gas escape velocity allowed by the package or casing is lower than the speed at which it flows into the closed volume of the package or casing from the pressurized container. More preferably, the substantially impermeable package of the present invention has a permeability to HFA p227 that is less than or equal to about 0.25 cc of HFA p227 per square meter of package per day at a pressure of about 1 bar and at about room temperature, or a permeability to HFA 134a that is less or equal to about 4.1 cc of HFA 134a per square meter of package per day at a pressure of about 1 bar and at about room temperature. Also, in this context, "impenetrable" to the propellant means impenetrable by the HFA propellant used in the present invention.

Flexible material for making packages

The preferred flexible material for making the package is laminate, although other materials can be used satisfactorily. The main limitations are that the package material must be substantially impermeable to atmospheric moisture, and impermeable or substantially impermeable to the HFA propellant being used.

The laminate used in making packages generally consists of several layers of material that are either extruded together or bonded together to form what appears to be a single laminate film. As an example, a suitable laminate may have three layers adhesively laminated to one another: an inner layer, a barrier layer, and an outer layer. For example, Pharmaflex Ltd., part of Alcan Inc. (Cramlington, Northumberland, England) supplies laminate films that have three layers: 12 micron polyester / 9 micron aluminum foil / 50 micron polyethylene (product catalog LMP-F BRI/72/H1). Also, another laminate that can be used in this invention comprises polyester (16.9 gsm/12 micron, oriented in an acrylic shell)/low density polyethylene (20 gsm, painted white using titanium dioxide)/aluminum foil (24.3 gsm /9 micron)/polyethylene copolymer (5 gsm)/low density polyethylene (13 gsm)/linear low density polyethylene (37 gsm/40 micron).

The inner layer is located on the inner surface of the package (ie on the side in contact with the inhalation device) and is normally a thermoplastic layer and can be heat sealed. The usual material for the inner layer is polyethylene, but other polyolefin or cyclo-olefin materials can also be used. In addition, special materials such as ionomers are also often used to make the inner layer, for example, ionomer under the trade name Surlyn. The properties that distinguish these ionomer resins from other polyolefin heat sealing polymers are high clarity, high impact resistance, low lamination haze, tear resistance, scratch resistance, solid state toughness, and moisture impermeability.

The barrier layer is located between the inner and outer layers (i.e. it is sandwiched between the inner and outer layers) and gives the package impermeability, or substantial impermeability. Aluminum foil is commonly used for the barrier layer, although any metal that can be rolled into thin sheets can be satisfactorily used. A typical thickness of the aluminum foil layer is about 8 or 9 microns. Alternatively, the barrier layer can be metallized films, made of tin, iron, zinc, magnesium or other metals, which are vacuum- or spray-applied to the polymer surface as a coating.

The outer layer is located on the surface of the layer that serves as an obstacle, on the opposite side of the inner layer. The outer layer normally provides support, impact resistance, barrier layer protection and overall package durability. The commonly used material for the outer layer is polyester, although other materials, such as paper, can also be used.

Adhesives can be used to join the mentioned layers of material together. The adhesive layers are typically significantly less thick relative to the thickness of the substrate, heat sealable layers and/or protective layers they bond.

The number, size, and shape of the layers are not limited to only those layers shown in the drawings. Any number of layers with any relative surface area of any size and predetermined thickness may be used as long as the flexible package forms an enclosed volume that substantially prevents the penetration of water vapor and particulate material into an enclosed volume that is impermeable or substantially impermeable to HFA leakage from the MDI device.

Preferred exemplary thicknesses of the three layers include an outer layer of 1 to 40, more preferably 4 to 30, more preferably 10 to 23 microns, and most preferably 12 microns; a barrier layer of 1 to 100, more preferably 3 to 70, more preferably 5 to 50, more preferably 6 to 20 microns and most preferably 9 microns. For the inner layer, preferred exemplary thicknesses include thicknesses of 1 to 100, more preferably 5 to 70, more preferably 10 to 60, more preferably 20 to 55 microns, and most preferably 50 microns.

Preferred exemplary embodiments include a polyester film as the outer layer with a thickness in the range of 12 to 23 microns. The polyester film is laminated to the aluminum foil as a substrate layer with a thickness in the range of 6 to 20 microns. Aluminum foil is laminated to the inner layer as a polyethylene film with a thickness in the range of 20 to 50 microns.

Alternative preferred embodiments include an aluminum metallized polyester film laminated to the inner layer as noted above. Another embodiment includes a polyester film coated with silicon oxide and laminated to the inner layer as noted above. In yet another embodiment, a polyester film as an outer layer having a thickness in the range of 12 to 30 microns is laminated to an aluminum foil as a substrate layer having a thickness in the range of 6 to 20 microns, and the aluminum foil is laminated to a polyester film of 12 to 30 micron which is laminated to the inner layer as highlighted above. In another embodiment, a polypropylene film as an outer layer having a thickness in the range of 15 to 30 microns is laminated to an aluminum foil as a barrier layer having a thickness in the range of 6 to 20 microns, and the aluminum foil is laminated to the inner layer as pointed out above. Laminates in the present invention can be adhesively or extrusion laminated.

The laminate may be made of any of the materials described above and of any thickness as described above, so long as the final laminate is impermeable, or substantially impermeable, to HFA 134a or HFA p227.

The permeability, or significant impermeability, of laminates can be tested by various techniques known to those skilled in the art. For example, three pieces of disc with a diameter of 75 mm are cut from laminate material. The thickness of the laminate discs is then measured and recorded. The samples are then placed in the test chamber and vacuumed to 23°C for at least three hours. When the vacuum stabilizes, approximately 50 psi of HFA p227 thrust gas is applied to the top half of the cause disc, which represents the pressure release for the cylinder at lab temperature, while the bottom side is still under vacuum. A similar test can be performed using 30 psi of HFA 134a thrust gas applied to the top half of the disc specimen.

HFA adsorbent and gaseous substances

"HFA adsorbent" means a substance that has the ability to condense or retain HFA molecules on its surface or in its internal structure, an action often referred to as "adsorption" or "absorption". Examples of HFA adsorbents are selected from the group consisting of molecular sieves, activated clays (including, montmorillonite and bentonite clays, and other known activated clays, e.g. clays supplied by Colin Stewart Minchem Ltd, Cheshire, Great Britain), activated aluminum oxide, silicon oxide, zeolite, bauxite, and their mixtures. More conveniently, 10 A (Angstrom) molecular sieves.

This invention is not limited to any specific HFA adsorbent or specific gaseous substances. Although there are many different HFA adsorbents and there are different types of propellants, it is believed that any propellant can in principle be removed with a properly selected HFA adsorbent. Following the information disclosed in this invention, those skilled in the art are able to select the appropriate HFA adsorbent for the appropriate propellant gas. Practitioners can make an initial decision based on their knowledge and experience (for example, by evaluating factors such as the molecular size of the gaseous substances and the pore size of the HFA adsorbent as well as the electronic charge they carry) and then conduct tests (as disclosed herein or some other methods) to determine the actual performance of the selected HFA adsorbent against a given thrust gas. It may be necessary for individuals to repeat this process until a suitable HFA adsorbent is found.

As described in previous chapters, the applicants of this application have found that molecular sieves with a pore size of about 10 angstroms are effective HFA adsorption materials. Fitting about 4 grams of molecular sieve in a bag supplied by AtoFina (Solihull, England) under the trade name Siliporite, for example, has been found to be sufficient per packet to prevent packet inflation. More comprehensive technical information about molecular sieves and their other industrial applications can be found in the article "Molecular Sieves: Unique Moisture and Odor-Taste Control Material", by D. Hajdu, T.J. Dangieri and S.R. Dunne, TAPPI Polym., Lamintaions Coat. Conf. (1999), volume 2, p. 655-662, which is incorporated herein by reference.

Bag of HFA adsorbent

Although it is not necessary for the HFA adsorbent bag to be inside the package, it is usually preferred. HFA adsorbent bags are commercially available from many suppliers including Sud-Chemie (Middlewich, England). The bag, which looks like a tea bag, is usually made of synthetic fibers, such as polyamide or polyester fibers or fibers of their kind. Commercially available materials suitable for making HFA adsorbent bags include, for example, GDT-II from San-ei Corporation (Osaka, Japan) and Tyvek from Perfecseal (Londonderry, N. Ireland, Great Britain). However, suitable bags may be of other conventional shapes or designs and made of other permeable materials. The molecular sieve material contained within the bag is commercially available from several manufacturers. For example, AtoFina (Solihull, England) markets a molecular sieve under the trade name Siliporite.

Pressurized tank

A pressure tank is more suitable an MDI tank. The term "MDI" or "metered dose inhaler" means a unit consisting of a container and a device for dispensing the medicine. Exemplary pressurized containers for use in MDI are disclosed in patents WO 96/32151, WO 96/32345, WO 96/32150, WO 96/32099, and US patents 6,293,279, 6,253,762 and 6,149,892.

Most often, the MDI container and lid are made of aluminum or an aluminum alloy, although other materials unaffected by the shape of the drug may be used, such as stainless steel, copper alloy, or tin lining. The MDI container can also be made of glass or plastic. It is more convenient, however, for the MDI containers used in the present invention to be made of aluminum or an alloy thereof. It is even more convenient to use tanks made of reinforced aluminum or aluminum alloy. Such reinforced MDI containers are capable of withstanding extremely severe coating and vulcanization conditions, eg, extremely high temperatures, which may be required for certain fluorocarbon polymers.

Reinforced MDI tanks that have a reduced tendency to deform at high temperatures include MDI tanks that have sidewalls and a base of increased thickness, and MDI tanks that have a substantially ellipsoidal base (which increases the angle between the sidewalls and the base of the tank), which is better than a semicircular base. of standard MDI containers. MDI containers having an ellipsoidal base provide the further advantage of facilitating the coating process.

MDI containers of the present invention include MDI containers supplied by Presspart of Blackburn, Lancashire, UK or Neotechnic of Clitheroe, Lancashire, UK. MDI containers typically have a neck diameter of 20 millimeters, although any convenient neck diameter can be used and container heights vary from 30 millimeters to 60 millimeters.

While the fundamental novel features of the invention as applied to the preferred embodiment thereof have been described and highlighted herein, it should be understood that those skilled in the art may make various omissions and modifications and substitutions, in the form and details of the packages and methods described, without departing from the ideas of this invention. For example, all combinations of these elements and/or steps in a method that perform essentially the same function in the same manner to achieve the same results are expressly intended to be within the scope of this invention.

The invention is not limited to the embodiments described above, which are presented only as examples, but can be modified in various ways within the scope of protection defined by the patent claims in the appendix.

Claims (108)

1. A method for maintaining the closed volume of a sealed package at approximately ambient pressure, characterized in that the package contains a pressurized MDI (metered dose inhaler) container containing the drug, and an HFA (hydrofluoroalkane) propellant gas selected from the group consisting of HFA 134a and HFA p227, or their mixture; whereby the procedure consists of steps: (i) placing an effective amount of the HFA adsorbent material, and said pressurized container, in a sealable package; (ii) sealing the package so that the pressurized container and the adsorbent are in a closed volume within the package at a pressure approximately equal to the ambient; (iii) adsorption of the leaked HFA propellant gas in the HFA adsorbent material so that the enclosed volume is maintained at approximately ambient pressure. 2. The method according to claim 1, characterized in that the drug is selected from the group consisting of bronchodilators, antihistamines, pulmonary surfactants, antiviral agents, corticosteroids, anti-inflammatory agents, anticholinergics, and antibiotics. 3. The method according to claim 1 or 2, characterized in that the pressurized container MDI (metered dose inhaler) further contains one or more excipients selected from the group consisting of surfactants, preservatives, flavoring agents, antioxidants, agents to prevent the formation of clusters and co-solvents. 4. The method according to any one of claims 1 to 3, characterized in that the HFA propellant gas is HFA 134a. 5. The method according to any one of claims 1 to 3, characterized in that the HFA propellant gas is HFA p227. 6. The method according to any one of claims 1 to 5, characterized in that the HFA adsorbent material has the ability to adsorb HFA thrust gas up to about 25% of the weight of the adsorbent. 7. The method according to any one of claims 1 to 5, characterized in that the HFA gas adsorption material has the ability to adsorb HFA pressure gas up to about 20% of the weight of the adsorbent. 8. The method according to any one of claims 1 to 7, characterized in that the HFA adsorption material is a material selected from the group consisting of molecular sieves, active clays, active aluminum oxide, silicon oxide, zeolite, bauxite, and their mixture. 9. The method according to claim 8, characterized in that the HFA adsorption material is represented by 10 Å (Angstrom) molecular sieves. 10. The method according to claim 9, characterized in that the molecular sieves, in an amount of about 4 grams, absorb about 230 ml of HFA p227. 11. The method according to claim 9, characterized in that the molecular sieves, in an amount of about 4 grams, absorb about 230 ml of HFA 134a. 12. The method according to any one of claims 1 to 11, characterized in that the package is impermeable to HFA 134a. 13. The method according to any one of claims 1 to 12, characterized in that the package is impermeable to HFA p227. 14. The method according to any one of claims 1 to 12, characterized in that the packet is passed for HFA p227. 15. The method according to claim 14, characterized in that the package has a permeability for HFA p227 that is less than or equal to about 0.25 cc of HFA p227 per square meter of the package per day at a pressure of about 1 bar and at about room temperature. 16. The method according to claim 14, characterized in that the package has a permeability for HFA p227 that is less than or equal to about 0.15 cc of HFA p227 per square meter of the package per day at a pressure of about 1 bar and at about room temperature. 17. The method according to claim 14, characterized in that the package has a permeability for HFA p227 that is less than or equal to about 0.10 cc of HFA p227 per square meter of the package per day at a pressure of about 1 bar and at about room temperature. 18. The method according to claim 14, characterized in that the package has a permeability for HFA p227 that is less than or equal to about 0.05 cc of HFA p227 per square meter of the package per day at a pressure of about 1 bar and at about room temperature. 19. The method according to any one of claims 1 to 11 or 14, characterized in that the packet is passed for HFA 134a. 20. The method according to claim 19, characterized in that the package has a permeability for HFA 134a that is less than or equal to about 4.1 cc of HFA 134a per square meter of the package per day at a pressure of about 1 bar and at about room temperature. 21. The method according to claim 19, characterized in that the package has a permeability for HFA 134a that is less than or equal to about 3.5 cc of HFA 134a per square meter of package per day at a pressure of about 1 bar and at about room temperature. 22. The method according to claim 19, characterized in that the package has a permeability for HFA 134a that is less than or equal to about 2.5 cc of HFA 134a per square meter of the package per day at a flow of about 1 bar and at about room temperature. 23. The method according to claim 19, characterized in that the package has a permeability for HFA 134a that is less than or equal to about 1.5 cc of HFA 134a per square meter of the package per day at a pressure of about 1 bar and at about room temperature. 24. The method according to claim 19, characterized in that the package has a permeability for HFA 134a that is less than or equal to about 1.0 cc of HFA 134a per square meter of the package per day at a pressure of about 1 bar and at about room temperature. 25. The method according to claim 19, characterized in that the package has a permeability for HFA 134a that is less than or equal to about 0.5 cc of HFA 134a per square meter of package per day at a pressure of about 1 bar and at about room temperature. 26. The method according to any one of claims 1 to 25, characterized in that the package is made of metal, glass, or plastic, and selected from the group consisting of bottles, bags, drum-shaped boxes, and containers of irregular shape. 27. The method according to any one of claims 1 to 26, characterized in that the package is made of plastic. 28. The method according to claim 27, characterized in that the plastic is a flexible laminate having a barrier layer which gives said package permeability to HFA 134a and/or HFA p227. 29. The method according to claim 27, characterized in that the plastic is a flexible laminate having a barrier layer that renders said package impervious to HFA 134a and/or HFA p227. 30. The method according to claim 28 or 29, characterized in that said flexible laminate has three layers: polyester/aluminum/polyethylene, where the aluminum layer is located between the layers of polyester and polyethylene. 31. The method according to claim 28 or 29, characterized in that said barrier layer is made of aluminum foil. 32. The method according to any one of claims 1 to 31, characterized in that the sealed package is hermetically sealed by means of heat sealing, gluing, welding, soldering, mechanical fasteners or clips, or compression. 33. Use of HFA adsorbent to maintain the pressure of a closed volume within a sealed package at approximately ambient pressure, characterized in that the sealed package contains: (i) a pressurized MDI (metered dose inhaler) container containing the drug, and an HFA (hydrofluoroalkane) propellant gas selected from the group consisting of HFA 134a and HFA p227, or a mixture thereof; (ii) an effective amount of HFA adsorbent material; wherein the MDI pressurized container and the HFA adsorbent material are contained within the closed volume of the sealed package. 34. Use according to claim 33, characterized in that the drug is selected from the group consisting of bronchodilators, antihistamines, pulmonary surfactants, antiviral agents, corticosteroids, anti-inflammatory agents, anticholinergics, and antibiotics. 35. Use according to claim 33 or 34, characterized in that the pressurized container MDI (metered dose inhaler) further contains one or more excipients selected from the group consisting of surfactants, preservatives, flavoring agents, antioxidants, prevention agents formation of clusters and co-solvents. 36. Use according to any one of claims 33 to 35, characterized in that the HFA propellant is HFA 134a. 37. Use according to any one of claims 33 to 35, characterized in that the HFA propellant is HFA p227. 38. Use according to any one of claims 33 to 37, characterized in that the HFA adsorbent material has the ability to adsorb HFA thrust gas up to about 25% of the weight of the adsorbent. 39. Use according to any one of claims 33 to 37, characterized in that the HFA gas adsorption material has the ability to adsorb HFA pressure gas up to about 20% of the weight of the adsorbent. 40. Use according to any one of claims 33 to 39, characterized in that the HFA adsorption material is a material selected from the group consisting of molecular sieves, active clays, active aluminum oxide, silicon oxide, zeolite, bauxite, and their mixture. 41. Use according to claim 40, characterized in that the HFA adsorption material is represented by 10 A (Angstrom) molecular sieves. 42. Use according to claim 41, characterized in that the molecular sieves, in an amount of about 4 grams, absorb about 230 ml of HFA p227. 43. Use according to claim 41, characterized in that the molecular sieves, in an amount of about 4 grams, absorb about 230 ml of HFA 134a. 44. Use according to any one of claims 33 to 43, characterized in that the package is impermeable to HFA 134a. 45. Use according to any one of claims 33 to 42, characterized in that the package is impermeable to HFA p227. 46. Use according to any one of claims 33 to 42, characterized in that the packet is permeable to HFA p227. 47. Use according to claim 46, characterized in that the package has a permeability for HFA p227 that is less than or equal to about 0.25 cc of HFA p227 per square meter of package per day at a pressure of about 1 bar and at about room temperature. 48. Use according to claim 46, characterized in that the package has a permeability for HFA p227 that is less than or equal to about 0.15 cc of HFA p227 per square meter of package per day at a pressure of about 1 bar and at about room temperature. 49. Use according to claim 46, characterized in that the package has a permeability for HFA p227 that is less than or equal to about 0.10 cc of HFA p227 per square meter of package per day at a pressure of about 1 bar and at about room temperature. 50. Use according to claim 46, characterized in that the package has a permeability for HFA p227 that is less than or equal to about 0.05 cc of HFA p227 per square meter of package per day at a pressure of about 1 bar and at about room temperature. 51. Use according to any one of claims 33 to 43, characterized in that the packet is passable for HFA 134a. 52. Use according to claim 51, characterized in that the package has a permeability for HFA 134a that is less than or equal to about 4.1 cc of HFA 134a per square meter of package per day at a pressure of about 1 bar and at about room temperature. 53. Use according to claim 51, characterized in that the package has a permeability for HFA 134a that is less than or equal to about 3.5 cc of HFA 134a per square meter of package per day at a pressure of about 1 bar and at about room temperature. 54. Use according to claim 51, characterized in that the package has a permeability for HFA 134a that is less than or equal to about 2.5 cc of HFA 134a per square meter of package per day at a pressure of about 1 bar and at about room temperature. 55. Use according to claim 51, characterized in that the package has a permeability for HFA 134a that is less than or equal to about 1.5 cc of HFA 134a per square meter of package per day at a pressure of about 1 bar and at about room temperature. 56. Use according to claim 51, characterized in that the package has a permeability for HFA 134a that is less than or equal to about 1.0 cc of HFA 134a per square meter of package per day at a pressure of about 1 bar and at about room temperature. 57. Use according to claim 51, characterized in that the package has a permeability for HFA 134a that is less than or equal to about 0.5 cc of HFA 134a per square meter of package per day at a pressure of about 1 bar and at about room temperature. 58. Use according to any one of claims 33 to 57, characterized in that the package is made of metal, glass, or plastic, and is selected from the group consisting of bottles, bags, drum-shaped boxes, and irregularly shaped containers. 59. Use according to claim 58, characterized in that the package is made of plastic. 60. Use according to claim 59, characterized in that the plastic is a flexible laminate having a barrier layer that renders said package impervious to HFA 134a and/or HFA p227. 61. Use according to claim 59 or 60, characterized in that the plastic is a flexible laminate having a barrier layer which gives said package permeability to HFA 134a and/or HFA p227. 62. Use according to claim 60 or 61, characterized in that said flexible laminate has three layers: polyester/aluminum/polyethylene, where the aluminum layer is located between the layers of polyester and polyethylene. 63. Use according to claim 60 or 61, characterized in that said barrier layer is made of aluminum foil. 64. Use according to any one of claims 33 to 63, characterized in that the sealed package is hermetically sealed by heat sealing, gluing, welding, soldering, mechanical fasteners or clips, or compression. 65. Pharmaceutical product characterized by the fact that it consists of: (i) pressurized container MD1 (metered dose inhaler) containing the drug, and HFA (hydrofluoroalkane) propellant gas selected from the group consisting of HFA 134a and HFA p227, or their mixture; (ii) effective amounts of HFA adsorbent material; and (iii) a sealed package with a closed volume inside which there are a pressurized container and HFA adsorption material, wherein the sealed package is impermeable to the HFA propellant gas and the pressure within the sealed volume is approximately equal to the ambient pressure; and wherein the HFA adsorbent material is capable of adsorbing the HFA propellant gas so that the pressure within said closed volume is maintained constant, when the HFA propellant gas escapes from the pressurized container. 66. Pharmaceutical product according to claim 65, characterized in that the drug is selected from the group consisting of bronchodilators, antihistamines, pulmonary surfactants, antiviral agents, corticosteroids, anti-inflammatory agents, anticholinergics, and antibiotics. 67. A pharmaceutical product according to claim 65 or 66, characterized in that the pressurized container MDI (metered dose inhaler) further contains one or more excipients selected from the group consisting of surfactants, preservatives, flavoring agents, antioxidants, preventing the formation of clusters and co-solvents. 68. A pharmaceutical product according to any one of claims 65 to 67, characterized in that the HFA propellant is HFA 134a. 69. A pharmaceutical product according to any one of claims 65 to 67, characterized in that the HFA propellant is HFA p227. 70. A pharmaceutical product according to any one of claims 65 to 69, characterized in that the HFA adsorbent material has the ability to adsorb HFA thrust gas up to about 25% of the weight of the adsorbent. 71. A pharmaceutical product according to any one of claims 65 to 69, characterized in that the HFA gas adsorption material has the ability to adsorb HFA pressure gas up to about 20% of the weight of the adsorbent. 72. Pharmaceutical product according to any one of claims 65 to 71, characterized in that the HFA adsorption material consists of a material selected from the group consisting of molecular sieves, active clays, active aluminum oxide, silicon oxide, zeolite, bauxite, and their mixture . 73. Pharmaceutical product according to claim 72, characterized in that the HFA adsorption material is represented by 10 Å (Angstrom) molecular sieves. 74. Pharmaceutical product according to claim 73, characterized in that the molecular sieves, in an amount of about 4 grams, absorb about 230 ml of HFA p227. 75. Pharmaceutical product according to claim 73, characterized in that the molecular sieves, in an amount of about 4 grams, absorb about 230 ml of HFA 134a. 76. A pharmaceutical product according to any one of claims 65 to 75, characterized in that the package is impermeable to HFA 134a. 77. A pharmaceutical product according to any one of claims 65 to 75, characterized in that the package is impermeable to HFA p227. 78. A pharmaceutical product according to any one of claims 65 to 77, characterized in that the package is made of metal, glass, or plastic, and selected from the group consisting of bottles, bags, drum-shaped boxes, and irregularly shaped containers . 79. Pharmaceutical product according to claim 71, characterized in that the package is made of plastic. 80. A pharmaceutical product according to claim 79, characterized in that the plastic is a flexible laminate having a barrier layer that renders said package impervious to HFA 134a and/or HFA p227. 81. Pharmaceutical product according to claim 80, characterized in that said flexible laminate has three layers: polyester/aluminum/polyethylene, where the aluminum layer is located between the layers of polyester and polyethylene. 82. Pharmaceutical product according to claim 80, characterized in that said barrier layer is made of aluminum foil. 83. A pharmaceutical product according to any one of claims 65 to 82, characterized in that the sealed package is hermetically sealed by heat sealing, gluing, welding, soldering, mechanical closures or clips, or compression. 84. Pharmaceutical products characterized by the fact that they contain: (i) a pressurized MDI (metered dose inhaler) container containing the drug, and an HFA (hydrofluoroalkane) propellant gas selected from the group consisting of HFA 134a and HFA p227, or a mixture thereof; (ii) an effective amount of HFA adsorbent material; and (iii) a sealed package with a closed volume containing a pressurized container and HFA adsorption material, wherein the sealed package is impermeable to the HFA propellant gas and the pressure within the sealed volume is approximately equal to the ambient pressure; wherein the HFA adsorbent material is capable of adsorbing the HFA propellant gas so that the pressure within said closed volume is maintained constant, when the HFA propellant gas escapes from the pressurized container; and wherein the package has a permeability to HFA p227 that is less than or equal to about 0.25 cc of HFA p227 per square meter of package per day at a pressure of about 1 bar and at about room temperature, or has a permeability to HFA 134a that is less than or equal to 4.1 cc of HFA 134a per square meter of package per day at a pressure of about 1 bar and at about room temperature. 85. A pharmaceutical product according to claim 84, wherein the package has a permeability to HFA p227 that is less than or equal to about 0.15 cc of HFA p227 per square meter of package per day at a pressure of about 1 bar and at about room temperature. 86. A pharmaceutical product according to claim 84, wherein the package has a permeability to HFA p227 that is less than or equal to about 0.10 cc of HFA p227 per square meter of package per day at a pressure of about 1 bar and at about room temperature. 87. A pharmaceutical product according to claim 84, wherein the package has a permeability to HFA p227 that is less than or equal to about 0.05 cc of HFA p227 per square meter of package per day at a pressure of about 1 bar and at about room temperature. 88. The pharmaceutical product according to claim 84, characterized in that the package has a permeability for HFA 134a that is less than or equal to about 3.5 cc of HFA 134a per square meter of package per day at a pressure of about 1 bar and at about room temperature. 89. The pharmaceutical product according to claim 84, characterized in that the package has a permeability for HFA 134a that is less than or equal to about 2.5 cc of HFA 134a per square meter of package per day at a pressure of about 1 bar and at about room temperature. 90. A pharmaceutical product according to claim 84, characterized in that the package has a permeability for HFA 134a that is less than or equal to about 1.5 cc of HFA 134a per square meter of package per day at a pressure of about 1 bar and at about room temperature. 91. A pharmaceutical product according to claim 84, wherein the package has a permeability for HFA 134a that is less than or equal to about 1.0 cc of HFA 134a per square meter of package per day at a pressure of about 1 bar and at about room temperature. 92. A pharmaceutical product according to claim 84, wherein the package has a permeability for HFA 134a that is less than or equal to about 0.5 cc of HFA 134a per square meter of package per day at a pressure of about 1 bar and at about room temperature. 93. A pharmaceutical product according to any one of claims 84 to 92, characterized in that the drug is selected from the group consisting of bronchodilators, antihistamines, pulmonary surfactants, antiviral agents, corticosteroids, anti-inflammatory agents, anticholinergics, and antibiotics. 94. A pharmaceutical product according to any one of claims 84 to 93, characterized in that the pressurized container MDI (metered dose inhaler) further contains one or more excipients selected from the group consisting of surfactants, preservatives, flavoring agents, antioxidants , anti-caking agents and co-solvents. 95. A pharmaceutical product according to any one of claims 84 to 94, characterized in that the HFA propellant gas is HFA 134a. 96. A pharmaceutical product according to any one of claims 84 to 94, characterized in that the HFA propellant is HFA p227. 97. A pharmaceutical product according to any one of claims 84 to 96, characterized in that the HFA adsorbent material has the ability to adsorb HFA thrust gas up to about 25% by weight of the adsorbent. 98. A pharmaceutical product according to any one of claims 84 to 96, characterized in that the HFA gas adsorption material has the ability to adsorb HFA thrust gas up to about 20% of the weight of the adsorbent. 99. Pharmaceutical product according to any one of claims 84 to 98, characterized in that the HFA adsorption material is a material selected from the group consisting of molecular sieves, active clays, active aluminum oxide, silicon oxide, zeolite, bauxite, and their mixture . 100. Pharmaceutical product according to claim 99, characterized in that the HFA adsorption material is represented by 10 Å (Angstrom) molecular sieves. 101. Pharmaceutical product according to claim 100, characterized in that the molecular sieves, in an amount of about 4 grams, absorb about 230 ml of HFA p227. 102. Pharmaceutical product according to claim 100, characterized in that the molecular sieves, in an amount of about 4 grams, absorb about 230 ml of HFA 134a. 103. A pharmaceutical product according to any one of claims 84 to 102, characterized in that the package is made of metal, glass, or plastic, and selected from the group consisting of bottles, bags, drum-shaped boxes, and irregularly shaped containers . 104. Pharmaceutical product according to claim 103, characterized in that the package is made of plastic. 105. A pharmaceutical product according to claim 104, characterized in that the plastic is a flexible laminate having a barrier layer that gives said package permeability to HFA 134a and/or HFA p227. 106. Pharmaceutical product according to claim 105, characterized in that said flexible laminate has three layers: polyester/aluminum/polyethylene, where the aluminum layer is located between the layers of polyester and polyethylene. 107. Pharmaceutical product according to claim 105, characterized in that said barrier layer is made of aluminum foil. 108. A pharmaceutical product according to any one of claims 84 to 107, characterized in that the sealed package is hermetically sealed by heat sealing, gluing, welding, soldering, mechanical closures or clamps, or compression.