KR100995184B1 - Packaging Method for Pressurized Containers and Packaged Pharmaceutical Product Using the Same - Google Patents

Abstract

Provided is a method for maintaining the intrinsic volume of a sealed package at atmospheric pressure, wherein the package consists of a pressurized container comprising a drug and a hydrofluoroalkane (HFA) propellant selected from the group consisting of HFA 134a, HFA p227, or mixtures thereof. Wherein the method of maintaining the intrinsic volume comprises (1) placing an effective amount of HFA adsorbent material and a pressurized vessel in a sealable packaging; (2) sealing the package at a pressure equal to atmospheric pressure such that the pressurized vessel and the adsorbent may be included in the interior volume of the package; And (3) absorbing the HFA propellant leaked by the HFA adsorbent material to maintain the intrinsic volume at atmospheric pressure.

Intrinsic volume, hydrofluoroalkane, propellant, pressurized vessel

Description

Packaging Method for Pressurized Containers and Packaged Pharmaceuticals Using the Same {Packaging Method for Pressurized Containers and Packaged Pharmaceutical Product Using the Same}

The present invention relates to a method and a packaging material for packaging a pressurized container suitable for relatively long term storage. More specifically, the present invention is a packaging material using an HFA adsorbent material, for example, a molecular sieve, which can absorb or adsorb the propellant gas gradually leaking from the pressurized vessel, thereby preventing the packaging material from expanding. And a packaging method.

Pressurized containers, such as inhalers, should be packed with impermeable packaging to prevent moisture from entering the atmosphere. Using such an impermeable packaging material accumulates progressively leaking propellant gas from the pressurized container, thereby releasing the sealing of the packaging material. This problem has been highlighted by replacing hydrofluoroalkane propellants (e.g., HFA-134a and HFA-227) instead of chlorofluorocarbons (CFC), which have traditionally been used for environmental reasons.

U.S. Patent 6,179,118 B1, 6,119,853, 6,352,152 solved this problem by using a soft packaging material that "water cannot pass through and propellant gas can pass through." Although this approach seemed to solve the problem well, Applicants had difficulty creating a soft packaging that is water-impermeable and permeable to gases, and the resulting packaging material was substantially "one-way valve". It worked together. Judging from the above patent content, it seems that a high level of technology is required to produce such a flexible packaging material, and it is more expensive. Therefore, there is a need for a simpler and more understandable way to solve the expansion problem in packaging pressurized containers.

In addition, in US Pat. Nos. 6,179,118 B1, 6,119,853, 6,352,152, the packaging material that can prevent the accumulation of gas in the packaging material has a limitation in the permeability of the packaging material of the propellant gas, and the speed at which the propellant gas is released from the container also appears to be limited.

Accordingly, there is a need for an improved chemical made of packaging that can maintain the encapsulation volume of the sealed packaging at atmospheric pressure in the event of a leak of a portion of the HFA propellant gas while preventing or substantially preventing the escape of HFA gas from the packaging.

Summary of the Invention

It is a primary object of the present invention to provide new packaging materials which can reduce or eliminate the swelling problems commonly found in conventional packaging methods in pressurized inhalers. Another object of the present invention is to provide a simpler method than the prior art method in solving the expansion problem. It is yet another object of the present invention to provide a new packaging material for a pressure inhaler that can eliminate or reduce the escape of HFA propellant gas from the packaging material commonly found in conventional packaging methods for pressure inhalers. Another object of the present invention is to provide a method for maintaining the encapsulation volume of a sealed package at atmospheric pressure, wherein the package comprises a HFA (hydrofluoroalkane) propellant leaking from the pressurized container.

The mechanism by which the HFA adsorbent material does not expand the packaging is believed to be achieved by trapping the propellant gas that gradually leaks from the pressurized container.

Various novel features that characterize the invention are particularly well exemplified in the appended claims, which are part of this disclosure. BRIEF DESCRIPTION OF DRAWINGS To better understand the present invention, its operational advantages, and the specific purposes that can be obtained using the same, reference numerals are set forth in the drawings and are described below in describing an embodiment of the present invention.

FIG. 1 is a graph summarizing studies showing that molecular sieves are effective HFA adsorbents for trapping propellant gas in the atmosphere and thereby prevent packaging expansion.

Figure 2 shows the moisture fraction absorbed by the molecular sieve after the first hour of exposure to the atmosphere.

Figure 3 shows the percentage of moisture absorbed by the same molecular sieve used in Figure 2 during 12 hours of exposure.

4 and 5 show that the molecular sieve's ability to absorb propellant gas is reduced when the molecular sieve is pre-exposed to moisture at different time intervals.

Figure 6 illustrates a typical metered dose (pressurized container) inhaler package according to the present invention.

(1) In a first embodiment, the present invention provides a method for maintaining the intrinsic volume of a sealed package at atmospheric pressure, wherein the package includes HFA (hydroflo) selected from the group consisting of drugs, HFA 134a and HFA p227 or mixtures thereof. A pressurized MDI (measured dose of inhaler) container comprising an oralcane) propellant, the method of maintaining the volume consisting of the following steps;

(i) placing the effective amount of HFA adsorbent material and the pressurized container in a package to be sealed;

(ii) sealing the packaging to place the pressurized container and adsorbent in the packaging volume in the packaging at a pressure equal to atmospheric pressure; And

(iii) absorbing any leaked HFA propellant into the HFA adsorbent such that the enclosed volume is maintained at atmospheric pressure.

(2) In another embodiment, the invention provides a method according to embodiment (1), wherein the drug is a bronchodilator, an antihistamine, a pulmonary surfactant, an antiviral agent, a corticosteroid, an anti-inflammatory agent, an anticholinergic agent , And antibacterial agents.

(3) In another embodiment, the invention provides a method according to embodiment (1) or (2), wherein the pressurized MDI (measured dose of inhaler) container is a surfactant, preservative, flavoring agent, antioxidant, And one or more excipients selected from the group consisting of anti-coagulant and co-solvent.

(4) In another embodiment, the present invention provides a method according to any one of embodiments (1) to (3), wherein the HFA propellant is HFA 134a.

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

(6) In another embodiment, the present invention provides a method according to any one of embodiments (1) to (5), wherein the HFA adsorbent material is capable of absorbing HFA propellant up to 25% of the adsorbent weight. have.

(7) In another embodiment, the present invention provides a method according to any one of embodiments (1) to (5), wherein the HFA gas adsorbent material will absorb the HFA propellant up to 20% of the adsorbent weight. Can be.

(8) In another embodiment, the present invention provides a method according to any one of embodiments (1) to (7), wherein the HFA adsorbent material is a molecular sieve, activated soil, activated alumina, silica, zeolite , Bakecycles and mixtures thereof.

(9) In another embodiment, the present invention provides a method according to embodiment (8), wherein the HFA adsorbent material is 10 kPa (Angstrom) molecular sieve.

(10) In another embodiment, the present invention provides a method according to embodiment (9), wherein the molecular sieve can absorb about 230 ml HFA p227 in an amount of about 4 g.

(11) In another embodiment, the present invention provides a method according to embodiment (9), wherein the molecular sieve can absorb about 230 ml HFA 134a in an amount of about 4 g.

(12) In another embodiment, the present invention provides a method according to any one of embodiments (1) to (11), wherein HFA 134a cannot penetrate the packaging.

(13) In another embodiment, the present invention provides a method according to any one of embodiments (1) to (12), wherein HFA p227 cannot penetrate the packaging.

(14) In another embodiment, the present invention provides a method according to any one of embodiments (1) to (12), wherein HFA p227 can penetrate the packaging.

(15) In another embodiment, the present invention provides a method according to embodiment (14), wherein HFA p227 can permeate the packaging material and the permeation amount is about 0.25 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(16) In another embodiment, the present invention provides a method according to embodiment (14), wherein HFA p227 can permeate the packaging material and the permeation amount is about 0.15 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(17) In another embodiment, the present invention provides a method according to embodiment (14), wherein HFA p227 can permeate the packaging material and the permeation amount is about 0.10 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(18) In another embodiment, the present invention provides a method according to embodiment (14), wherein HFA p227 can permeate the packaging material and the permeation amount is about 0.05 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(19) In another embodiment, the present invention provides a method according to embodiments (1) to (11) or (14), wherein HFA 134a can penetrate the packaging.

(20) In another embodiment, the present invention provides a method according to embodiment (19), wherein the HFA 134a can permeate the packaging material and the permeation amount is about 4.1 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(21) In another embodiment, the present invention provides a method according to embodiment (19), wherein the HFA 134a can permeate the packaging material and the permeation amount is about 3.5 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(22) In another embodiment, the present invention provides a method according to embodiment (19), wherein the HFA 134a can permeate the packaging material and the permeation amount is about 2.5 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(23) In another embodiment, the present invention provides a method according to embodiment (19), wherein HFA 134a can permeate the packaging material and the permeation amount is about 1.5 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(24) In another embodiment, the present invention provides a method according to embodiment (19), wherein the HFA 134a can permeate the packaging material and the permeation amount is about 1.0 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(25) In another embodiment, the present invention provides a method according to embodiment (19), wherein the HFA 134a can permeate the packaging material and the permeation amount is about 0.5 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(26) In another embodiment, the present invention provides a method according to any of embodiments (1) to (25), wherein the packaging is made of metal, glass or plastic, and the bottle, bag, drum box And irregularly shaped containers.

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

(28) In another embodiment, the present invention provides a method according to embodiment (27), wherein if the HFA 134a or HFA p227 can penetrate the packaging, the plastic may be a flexible laminate having a barrier layer. do.

(29) In another embodiment, the present invention provides a method according to embodiment (27), wherein if HFA 134a or HFA p227 cannot penetrate the packaging, the plastic may be a flexible laminate having a barrier layer. do.

(30) In another embodiment, the present invention provides a method according to embodiment (28) or (29), wherein the soft laminate has three layers of polyester / aluminum / polyethylene, wherein the aluminum layer is polyester It is located between the layer and the polyethylene layer.

(31) In another embodiment, the present invention provides a method according to embodiment (28) or (29), wherein the barrier layer is made of aluminum foil.

(32) In another embodiment, the present invention provides a method according to any one of embodiments (1) to (31), wherein the sealed packaging material is heat-sealed, bonded, welded, soldered, mechanical sealed, Or by clamping or pressing.

(33) In another embodiment, the present invention provides the use of an HFA adsorbent used to maintain the pressure of the intrinsic volume of a sealed package at atmospheric pressure, wherein the sealed package includes

(i) a pressurized MDI (measured dose of inhaler) container comprising a drug and an HFA (hydrofluoroalkane) propellant selected from the group consisting of HFA 134a and HFA p227 or mixtures thereof;

(ii) an effective amount of HFA adsorbent material; Here, the pressurized MDI vessel and the HFA adsorbent material are located in the encapsulation volume of the sealed packaging.

(34) In another embodiment, the invention provides a use according to embodiment (33), wherein the drug is a bronchodilator, antihistamine, pulmonary surfactant, antiviral, corticosteroid, anti-inflammatory, anti-cholinergic , And antibiotics.

(35) In another embodiment, the present invention provides a use according to embodiment (33) or (34), wherein the pressurized MDI (measured dose of inhaler) container is a surfactant, preservative, fragrance, antioxidant, And one or more excipients selected from the group consisting of anti-coagulant and co-solvent.

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

(37) In another embodiment, the present invention provides the use of any one of embodiments 33-35, wherein the HFA propellant is HFA p227.

(38) In another embodiment, the present invention provides a use according to any one of embodiments (33) to (37), wherein the HFA adsorbent material is capable of absorbing HFA propellant up to 25% of the adsorbent weight. have.

(39) In another embodiment, the present invention provides a method according to any one of embodiments (33) to (37), wherein the HFA gas adsorbent material is capable of absorbing HFA propellant up to 20% of the adsorbent weight. Can be.

(40) In another embodiment, the present invention provides a use according to any one of embodiments (33) to (39), wherein the HFA adsorbent material is a molecular sieve, activated soil, activated alumina, silica, zeolite , Bakecycles and mixtures thereof.

(41) In another embodiment, the present invention provides a use according to embodiment 40, wherein the HFA adsorbent material is 10 kPa (Angstrom) molecular sieve.

(42) In another embodiment, the present invention provides a use according to embodiment (41), wherein the molecular sieve can absorb about 230 ml HFA p227 in an amount of about 4 g.

(43) In another embodiment, the present invention provides a use according to embodiment (41), wherein the molecular sieve can absorb about 230 ml HFA 134a in an amount of about 4 g.

(44) In another embodiment, the present invention provides a use according to any one of embodiments (33) to (43), wherein HFA 134a cannot penetrate the packaging.

(45) In another embodiment, the present invention provides a use according to any one of embodiments (33) to (43), wherein HFA p227 cannot penetrate the packaging.

(46) In another embodiment, the present invention provides a use according to any one of embodiments (33) to (42), wherein HFA p227 can penetrate the packaging.

(47) In another embodiment, the present invention provides a use according to embodiment (46), wherein HFA p227 can permeate the packaging material and the permeation amount is about 0.25 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(48) In another embodiment, the present invention provides a use according to embodiment (46), wherein HFA p227 can permeate the packaging material and the permeation amount is about 0.15 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(49) In another embodiment, the present invention provides a use according to embodiment (46), wherein HFA p227 can permeate the packaging material and the permeation amount is about 0.10 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(50) In another embodiment, the present invention provides a use according to embodiment (46), wherein HFA p227 can permeate the packaging material and the permeation amount is about 0.05 per square meter of packaging material per day at 1 bar atmosphere and about room temperature. cc or less.

(51) In another embodiment, the present invention provides a use according to embodiments 33-43, wherein HFA 134a can penetrate the packaging.

(52) In another embodiment, the present invention provides a use according to embodiment 51, wherein HFA 134a can permeate the packaging material and the permeation amount is about 4.1 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(53) In another embodiment, the present invention provides a use according to embodiment 51, wherein HFA 134a can permeate the packaging material and the permeation amount is about 3.5 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(54) In another embodiment, the present invention provides a use according to embodiment (51), wherein HFA 134a can permeate the packaging material and the permeation amount is about 2.5 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(55) In another embodiment, the present invention provides a use according to embodiment 51, wherein HFA 134a can permeate the packaging material and the permeation amount is about 1.5 per square meter of packaging material per day at 1 bar atmosphere and about room temperature. cc or less.

(56) In another embodiment, the present invention provides a use according to embodiment 51, wherein HFA 134a can permeate the packaging material and the permeation amount is about 1.0 per square meter of packaging material per day at 1 bar atmosphere and about room temperature. cc or less.

(57) In another embodiment, the present invention provides a method according to embodiment 51, wherein HFA 134a can permeate the packaging material and the permeation amount is about 0.5 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(58) In another embodiment, the present invention provides a use according to any one of embodiments 33 to 57, wherein the packaging is made of metal, glass or plastic, and the bottle, bag, drum box And irregularly shaped containers.

(59) In another embodiment, the present invention provides a use according to embodiment 58, wherein the packaging is made of plastic.

(60) In another embodiment, the present invention provides a use according to embodiment (59), wherein the plastic has a barrier layer to make the packaging impermeable to HFA 134a or HFA p227. Becomes

(61) In another embodiment, the present invention provides a use according to embodiment (59) or (60), wherein in order to make a packaging material through which HFA 134a or HFA p227 can permeate, the plastic is soft with a barrier layer. It becomes a laminate.

(62) In another embodiment, the present invention provides a use according to embodiment (60) or (61), wherein the soft laminate has three layers of polyester / aluminum / polyethylene, wherein the aluminum layer is polyester It is located between the layer and the polyethylene layer.

(63) In another embodiment, the present invention provides a use according to embodiment (60) or (61), wherein the barrier layer is made of aluminum foil.

(64) In another embodiment, the present invention provides a use according to any one of embodiments (33) to (63), wherein the sealed packaging material is heat-sealed, bonded, welded, soldered, mechanical sealed, Or by clamping or pressing.

(65) In the first embodiment, the present invention

(i) a pressurized MDI (measured dose of inhaler) container comprising an HFA (hydrofluoroalkane) propellant selected from the group consisting of drug, HFA 134a and HFA p227 or mixtures thereof;

(ii) HFA adsorbent material effective amount;

(iii) Provide a drug consisting of a sealed packaging having an intrinsic volume in which the pressurized container and the HFA adsorbent material are located. Wherein the HFA propellant cannot penetrate the sealed package and the pressure in the interior volume of the package is approximately equal to atmospheric pressure;

The HFA adsorbent material can absorb the HFA propellant, thereby maintaining a constant in-volume pressure in the event of any leakage of the HFA propellant from the pressurized vessel.

(66) In another embodiment, the present invention provides a medicament according to embodiment 65, wherein the medicament is a bronchodilator, an antihistamine, a pulmonary surfactant, an antiviral agent, a corticosteroid, an anti-inflammatory agent, an anticholinergic agent. , And antibiotics.

(67) In another embodiment, the present invention provides a drug according to embodiment 65 or 66, wherein the pressurized MDI (measured dose of inhaler) container is a surfactant, preservative, fragrance, antioxidant, And one or more excipients selected from the group consisting of anti-coagulants and co-solvents.

(68) In another embodiment, the present invention provides the drug of any one of embodiments 65-67, wherein the HFA propellant is HFA 134a.

(69) In another embodiment, the present invention provides the drug of any one of embodiments 65-67, wherein the HFA propellant is HFA p227.

(70) In another embodiment, the invention provides a medicament according to any one of embodiments (65) to (69), wherein the HFA adsorbent material is capable of absorbing HFA propellant up to 25% of the adsorbent weight. have.

(71) In another embodiment, the present invention provides a medicament according to any one of embodiments (65) to (69), wherein the HFA adsorbent material is capable of absorbing HFA propellant up to 20% of the adsorbent weight. have.

(72) In another embodiment, the present invention provides a medicament according to any one of embodiments (65) to (71), wherein the HFA adsorbent material is a molecular sieve, activated soil, activated alumina, silica, zeolite , Bakecycles and mixtures thereof.

(73) In another embodiment, the present invention provides a drug according to embodiment 72, wherein the HFA adsorbent material is 10 kPa (Angstrom) molecular sieve.

(74) In another embodiment, the present invention provides a drug according to embodiment (73), wherein the molecular sieve can absorb about 230 ml HFA p227 in an amount of about 4 g.

(75) In another embodiment, the present invention provides a drug according to embodiment (73), wherein the molecular sieve can absorb about 230 ml HFA 134a in an amount of about 4 g.

(76) In another embodiment, the present invention provides a medicament according to any one of embodiments (65) to (75), wherein HFA 134a cannot penetrate the packaging.

(77) In another embodiment, the present invention provides a medicament according to any one of embodiments (65) to (76), wherein HFA p227 cannot penetrate the packaging.

(78) In another embodiment, the present invention provides a drug according to any one of embodiments (65) to (77), wherein the packaging is made of metal, glass or plastic, and the bottle, bag, drum box box) and irregularly shaped containers.

(79) In another embodiment, the present invention provides a drug according to embodiment (71), wherein the packaging is made of plastic.

(80) In another embodiment, the present invention provides a drug according to embodiment 79, wherein the plastic is a flexible laminate with a barrier layer such that HFA 134a or HFA p227 cannot penetrate the packaging. .

(81) In another embodiment, the present invention provides a drug according to embodiment 80, wherein the soft laminate has three layers of polyester / aluminum / polyethylene, wherein the aluminum layer is a polyester layer and a polyethylene layer Located in between.

(82) In another embodiment, the present invention provides a drug according to embodiment 80, wherein the barrier layer is made of aluminum foil.

(83) In another embodiment, the present invention provides a drug according to any one of embodiments 65-82, wherein the sealed packaging material is heat-sealed, bonded, welded, soldered, mechanical sealed, Or by clamping or pressing.

(84) In the first embodiment, the present invention

(i) a pressurized MDI (measured dose of inhaler) container comprising an HFA (hydrofluoroalkane) propellant selected from the group consisting of drug, HFA 134a and HFA p227 or mixtures thereof;

(ii) HFA adsorbent material effective amount;

(iii) providing a medicament consisting of a sealed package having a sealed volume in which the pressurized container and the HFA adsorbent material are located;

Wherein the HFA propellant cannot penetrate the sealed packaging material and the pressure in the inherent volume of the packaging material is approximately equal to atmospheric pressure;

Since the HFA adsorbent material can absorb the HFA propellant, the pressure in the intrinsic volume can be kept constant in the event of any leakage of the HFA propellant from the pressurized vessel;

HFA p227 can permeate the packaging material, the permeation amount is about 0.25 cc or less per square meter of packaging material per day at 1 bar air pressure and about room temperature, HFA 134a can permeate the packaging material, and the permeation amount is per day at 1 bar air pressure and about room temperature Provide drugs with approximately 4.1 cc or less per square meter of packaging.

(85) In another embodiment, the present invention provides a drug according to embodiment 84, wherein HFA p227 can permeate the packaging material, the permeation amount being about 0.15 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(86) In another embodiment, the present invention provides a drug according to embodiment 84, wherein HFA p227 can permeate the packaging material and the permeation amount is about 0.10 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(87) In another embodiment, the present invention provides a drug according to embodiment 84, wherein HFA p227 can permeate the packaging material and the permeation amount is about 0.05 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(88) In another embodiment, the present invention provides a drug according to embodiment 84, wherein the HFA 134a can permeate the packaging material and the permeation amount is about 3.5 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(89) In another embodiment, the present invention provides a drug according to embodiment 84, wherein HFA 134a can permeate the packaging material, the permeation amount being about 2.5 per square meter of packaging material per day at 1 bar atmosphere and about room temperature. cc or less.

(90) In another embodiment, the present invention provides a drug according to embodiment 84, wherein the HFA 134a can permeate the packaging material and the permeation amount is about 1.5 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(91) In another embodiment, the present invention provides a drug according to embodiment 84, wherein the HFA 134a can permeate the packaging material and the permeation amount is about 1.0 per square meter of packaging material per day at 1 bar atmosphere and about room temperature. cc or less.

(92) In another embodiment, the present invention provides a drug according to embodiment 84, wherein the HFA 134a can permeate the packaging material and the permeation amount is about 0.5 per square meter of packaging material per day at 1 bar air pressure and about room temperature. cc or less.

(93) In another embodiment, the present invention provides a medicament according to embodiments (84) to (92), wherein the drug is a bronchodilator, antihistamine, pulmonary surfactant, antiviral, corticosteroid, anti-inflammatory , Anticholinergic, and antibiotic.

(94) In another embodiment, the present invention provides a medicine according to embodiment (84) or (93), wherein the pressurized MDI (measured dose of inhaler) container is a surfactant, preservative, fragrance, antioxidant, And one or more excipients selected from the group consisting of anti-coagulants and co-solvents.

(95) In another embodiment, the present invention provides the drug of any one of embodiments 84-94, wherein the HFA propellant is HFA 134a.

(96) In another embodiment, the present invention provides the drug of any one of embodiments 84-94, wherein the HFA propellant is HFA p227.

(97) In another embodiment, the present invention provides a medicament according to any one of embodiments (84) to (96), wherein the HFA adsorbent material is capable of absorbing HFA propellant up to 25% of the adsorbent weight. have.

(98) In another embodiment, the invention provides a medicament according to any one of embodiments (84) to (96), wherein the HFA adsorbent material is capable of absorbing HFA propellant up to 20% of the adsorbent weight. have.

(99) In another embodiment, the present invention provides a medicament according to any one of embodiments (84) to (98), wherein the HFA adsorbent material is a molecular sieve, activated soil, activated alumina, silica, zeolite , Bakecycles and mixtures thereof.

(100) In another embodiment, the present invention provides a drug according to embodiment (99), wherein the HFA adsorbent material is 10 kPa (Angstrom) molecular sieve.

(101) In another embodiment, the present invention provides a drug according to embodiment 100, wherein the molecular sieve can absorb about 230 ml HFA p227 in an amount of about 4 g.

(102) In another embodiment, the present invention provides a drug according to embodiment 100, wherein the molecular sieve can absorb about 230 ml HFA 134a in an amount of about 4 g.

(103) In another embodiment, the present invention provides a drug according to any one of embodiments (84) to (102), wherein the packaging is made of metal, glass or plastic, and the bottle, bag, drum box box) and irregularly shaped containers.

(104) In another embodiment, the present invention provides a drug according to embodiment 103, wherein the packaging is made of plastic.

(105) In another embodiment, the invention provides a drug according to embodiment 104, wherein the plastic is a flexible laminate with a barrier layer such that HFA 134a or HFA p227 cannot penetrate the packaging. .

(106) In another embodiment, the present invention provides a drug according to embodiment 105, wherein the soft laminate has three layers of polyester / aluminum / polyethylene, wherein the aluminum layer is a polyester layer and a polyethylene layer Located in between.

(107) In another embodiment, the present invention provides a drug according to embodiment 105, wherein the barrier layer is made of aluminum foil.

(108) In another embodiment, the present invention provides a drug according to any one of embodiments 84-107, wherein the sealed packaging material is heat-sealed, bonded, welded, soldered, mechanical sealed, Or by clamping or pressing.

(109) In another embodiment, the present invention provides a soft laminate composed of 12 micron polyester / 9 micron aluminum foil / 50 micron polyethylene in accordance with embodiments (30), (62), (81), (106) do.

It should be appreciated that the features of the invention, which are clearly described through separate embodiments, may be combined in one embodiment. In addition, for the sake of brevity, various features of the invention, which are described in a single embodiment, may also be represented separately or in any suitable combination.

HFA Adsorbent's Ability to Capture Propellant

It has been found that HFA adsorbent materials, especially molecular sieves, have the ability to remove (capture) propellant gases from the local environment. The present invention takes advantage of such properties of the HFA adsorbent material to encapsulate the HFA adsorbent in an opaque or substantially opaque and soft packaging as a means of preventing the packaging from expanding due to leaked propellant. Applicant encapsulates one or more HFA adsorbent materials in the packaging to absorb any leaked propellant, so that no moisture is introduced without worrying that the packaging of the soft packaging will break due to the expansion of the leaked propellant. It is possible to make a permeable soft packaging material. To determine the appropriate form and amount of HFA adsorbent material that can be used in each package for a pressure inhaler containing a specific propellant, Applicants conducted the following measurements to determine the sachet of approximately 4 g of 10 μg molecular sieves. ) Was able to remove (absorb) about 230 ml HFA-227 propellant.

Two methods were used to determine the absorption capacity of the molecular sieves. The first measurement method obtained approximate data on the amount of propellant that could be absorbed using a flowrap pack containing the active product. Based on the results obtained in the initial measurement method using only a container filled with propellant for the purpose of eliminating any possible effects on the active compound (eg drug), an accurate measurement method is found.

In the case of the initial measurement method, several samples (soft packaging materials for packing a pressurized inhaler containing the molecular sieve to be tested and the HFA-227 propellant) were prepared and tested in a Qualitek leak tester to determine the degree of sealing integrity. Check it. Place the package with the pressure inhaler valve facing upwards. Keeping the package as far as possible, turn the package over (with the valve facing down) and launch the aerosol a predetermined number of times and record the time it takes for each package to shrink. Care is taken to avoid such breaks in order to minimize the active material released by the propellant, and if the active material is released, the molecular sieve may be coated, which may reduce the adsorption performance of the molecular sieve. to be. Once the package is open, the presence of active substance on the surface of the molecular sieve is checked. If the active material is present, it means that the packaging material is turned upside down to prevent the active material from being released, thus affecting the adsorption rate. Initial measurement results are as follows;

All of the packages with up to 15 shots returned to their original size within 10 minutes, but the packaging with 20 shots expanded slightly after 15 minutes. The molecular sieve tests used showed that the product was deposited on the inside of the pouch and outside of the adsorbent sachet, although not on the surface of the adsorbent itself. This could be seen as a good criterion to judge the performance of the adsorbent before the more accurate method.

The following steps can be taken to ensure an accurate measurement:

1. Create multiple pressurized inhalers (aerosol cans) filled with HFA-227 propellant only. The number and weight made were recorded.

2. Make several soft packaging materials with one end open and record the numbers.

3. Place each aerosol can in the actuator and place in soft packaging.

4. Transfer the predetermined amount of molecular sieve from the unused polyethylene bag to a smaller minigrip bag. Tweezers are used to prevent the movement of moisture, and the molecular sieves are weighed and put back into each package.

5. Heat seal each package containing aerosol cans and molecular sieves immediately using AstraPack Heatsealer (installed to effectively seal these special packaging materials). Repeat this step for all packages.

6. The first five packages are left sealed. The reason is to evaluate the effect of taking moisture from the air of the actuator and the packaging material, which may be used as the basis for all other measurements.

7. The rest of the package is divided into five sets. Each set of cans performs a predetermined number of shots. The maximum number of shots is determined based on the information obtained from the initial measurement method. If you do more than 10 times, give yourself time to shrink until the next shot. All packaging sets should be stored for at least 24 hours to ensure maximum absorption of the propellant.

8. Leak test the packaging using a Qualitek leak tester to ensure that all packaging is properly sealed and that the data obtained are relevant. Discard results from packaging materials that fail the leak test.

9. Reopen each package and reweigh the molecular sieve and can. The molecular sieve is weighed first to prevent weight gain due to atmospheric moisture absorption.

10. The weight decreased in each can and the weight in the molecular sieve can be identified and averaged in each set. The data obtained can then be plotted to show the number of shots needed to reach the maximum absorption and the rate of weight increase (volume of gas) by the molecular sieve. Similarly, graphing the average weight exiting the can shows that the propellant was equally moved from the can to the molecular sieve until the final absorption of the molecular sieve was achieved (see FIG. 1).

As can be seen in FIG. 1, the comparison of the weight gain of the molecular sieve against the gas volume shows that the weight continues to increase until the propellant is absorbed 25 shots (corresponding to approximately 230 ml). This coincides with an increase in can weight reduction, while the weight of the molecular sieve remains constant. Thus, it can be concluded that about 4 g sachet of 10 Angstrom molecular sieves can remove (absorb) about 230 ml HFA-227 propellant.

Of course, since the HFA adsorbent material can be pre-exposed to the atmosphere for a period of time to absorb moisture in the atmosphere, the ability of the HFA adsorbent material to absorb the propellant may vary depending on the actual production line environment. The actual performance of the HFA adsorbent material that can absorb the propellant gas is limited by moisture absorption. Therefore, the advantages must be considered in practicing the present invention. In certain embodiments described herein, Applicants first measured the efficiency of the HFA adsorbent material close to the actual production line environment to absorb atmospheric moisture (FIGS. 2 and 3) and then absorbed the propellant under typical production conditions. The effect of atmospheric exposure time on the actual performance was examined (FIGS. 4, 5). The results of this study were used to determine the range of time exposure allowed during normal production, while maintaining the original target propellant uptake.

As can be seen in Figures 2 and 3, the water absorption during the first hour of exposure can reach 20% of maximum moisture absorption at 20 ° C / 45% RH (relative humidity) and 34% at 25 ° C / 60% RH. . Applicants also examined the difference in water absorption between the molecular sieves above and at the bottom of a large container, revealing that the molecular sieves directly exposed to the atmosphere can absorb moisture more quickly than the molecular sieves that are hidden due to the bottom of the container. lost. This shows that the effect is more persistent when the molecular sieve is in the reel form. These data will help you find the right way to handle molecular sieves in production environments.

In Figures 4 and 5, the molecular sieve is exposed to the production environment for a set period of time and immediately packaged using an Astrapack heatsealer. The packaging is exhausted if the seal is left for 10 minutes to cool the sutures and the aerosol (filled with only the propellant) is operated five times. Leave the package for another 10 minutes to allow the propellant to be absorbed. The operation is repeated until the maximum absorption of each molecular sieve is reached. Around 24 hours (the time at which the maximum absorption of the propellant is reached), each package is opened and the molecular sieve is weighed immediately. 4 shows that the grams of propellant absorbed by the 4g molecular sieve decrease after exposure to water for a specified number of hours. FIG. 5 shows the rate of propellant uptake per gram of molecular sieve at the same time zone as shown in FIG. 4. The purpose of this particular case is to absorb about 100 ml HFA-227 propellant (corresponding to 0.76 g) using a pouch containing 4 g molecular sieves. The data shown in Figures 4 and 5 show that this goal can be achieved even if the molecular sieve is normally exposed to atmospheric moisture in the production line for 30 minutes.

The findings indicate that embedding the HFA adsorbent in an impermeable or substantially impermeable packaging can be a simple, practical and effective solution to the problem of expanding the packaging in pressurized containers. Particularly when used to practice the present invention, the molecular sieve becomes an effective HFA adsorbent for package expansion.

Although various types of HFA adsorbents can be used and the effects on any given propellant can vary significantly, those skilled in the art have adopted some conventional testing methods, such as the studies described herein, to select specific leaks from pressurized vessels embedded in the packaging. It will be easy to determine the type and amount of HFA adsorbent material that is effective in reducing packaging expansion due to propellant.

Propellant

The propellant used in the present invention refers to a pharmacologically inert liquid having a boiling point in the range of about room temperature (25 ° C.) to -25 ° C. and having a high vapor pressure when used alone or in combination at room temperature. Upon activation of the MDI system, due to the high vapor pressure of the propellant in the MDA, a predetermined amount of drug composition is released through the metering valve, and the propellant vaporizes very quickly to disperse the drug particles. Propellants used in the present invention are suitably hydrofluoroalkanes such as hydrofluorocarbons and HFA-134a and HFA-227.

drug

As used herein, the term "drug" includes both currently available pharmacologically active drugs that can be used therapeutically and pharmacologically effective drugs that can be developed in the future that can be administered via the pulmonary route. Drugs include, for example, anesthetics such as codeine, dihydromorphine, erogatamine, fentanyl or morphine; Laryngitis (angina) preparations such as diltiazem; Antiallergic agents such as chromoglycate, ketotifen, nedocromil; Anti-inflammatory agents such as cephalosporins, penicillins, streptomycin, sulfonamides, tetracyclines, pentaimidines; Nuuraminidase inhibitors such as Relenza from GlaxoSmithkline and Ribavirin from ICN Pharmaceuticals, Inc; Antihistamines such as mnethapyfilene; Antitussives such as noscarpine; Salbutamol, Salmederol, Ephedrine, Adrenaline, Phenoterol, Forioterol, Isoprelinin, Phenylephrine, Phenylpropanolamine, Reproterol, Limiterol, Terbutalin, Isoetarin, Turobuterol, Orcy Bronchodilators such as prenaline, (-) 4-amino-3,5-dichloro-alpha-[[[6- [2- (2-pyridinyl) ethoxy] hexyl] -amino] methyl] benzenemethanol, epinephrine (Primatene), Formoterol (Foradil), Isoproterenol (Isuprel), Isotarin (Bronkosol), Metaproperenol (Alupent, Metaprel), Albuterol (Proventil, Ventolin), Terbutarin (Bricanyl, Beta including Brethine, Bitolterol (Tornalate), Pyrbuterol (Maxair), Salmeterol (Serevent), Salmeterol + Fluticasone Complex (Advair Diskus), Albuterol + Atrovent Complex (Combivent) Adrenaline; Sodium channel blockers such as amylolides, choline inhibitors such as ifpratropium, atropine or oxtrophyote; Hormones such as cortisone, hydrocortisone, prednisolone; Therapeutic proteins or peptides such as insulin or glucagon; NASACORT AQ ^® (triamcinolone acetonide), AZMACORT AQ ^® (triamcinolone acetonide) flunisolid, fluticasone, budesonide, triamcinolone acetonide, becloventone, budesonide flude Anti-inflammatory agents associated with the treatment of respiratory diseases, including steroids such as Aerobid, Fluticasone, Flovent, Salmeterol + Fluticasone Combination (Advair Diskus), and Triamcinolone (Azmacort), Intal ^® (chromoline sodium) Controlled release inhibitors such as nedocromyl sodium (Tilade); Leukotlin (LT) inhibitors, vascular active intestinal peptides (VIPs), tachykinin antagonists, bradkinin antagonists, endothelin antagonists, heparin purosemide, anti-adsorption molecules, cytokine modulators, biologically active Endonucleases, recombinant human (rh) DNase compounds, alpha-anti-trypsin, chromo-glycate disodium (DSCG); Waste surfactants such as compositions comprising lipids (TONGE et. Al, WO 99/09955); Lung surfactants (Devendra et. Al, Respir Res 2002, 3:19); Infasurf ^® (ONY); Curosurf ^® (Dey Laboratories); Exosurf ^® (Glaxo Wellcome); Survanta from Abbot; It may also be a drug selected from Surfaxin ^® Lung Surfactant (Discovery Laboratories).

The present invention encompasses a variety of hydrates, including the free acid, free base, salt, amine and semi-hydrate forms of such drugs, and in particular common pharmaceutically acceptable excipient materials known to those of skill in the art without further additives such as preservatives. It relates to a pharmaceutically acceptable preparation of a drug to be prepared.

Appropriate drug formulations do not include additional ingredients such as preservatives that significantly affect the formulation as a whole. Suitable preparations therefore consist of a pharmaceutically essential active drug and a pharmaceutically acceptable carrier (eg water or ethanol). However, when the drug is a liquid that does not contain an excipient, the preparation may consist only of the drug having a sufficiently low viscosity when sprayed using the dispenser of the present invention.

Drug preparations

Drug formulations that may be used in the present invention may be substantially free of preparation excipients such as surfactants or cosolvents. Such drug preparations are advantageous because they are substantially odorless or tasteless and are less irritating and toxic than preparations containing excipients. Thus, suitable drug formulations are optionally complexed with one or more other pharmacologically active substances and hydrofluorocarbon propellants or consist solely of drugs or physiologically acceptable salts or solvents.

Optionally, the aerosol formulations according to the invention may further comprise one or more cosolvents. C _2-6 aliphatic alcohols and polyols, such as glycerol, ethanol, isopropanol, propylene glycol, suitably in the amount necessary as an excipient alone or in combination with other excipients such as surfactants. It may be. Drug formulations include from 0.01 to 5% w / w, preferably from 0.1 to 5% w / w, for example from about 0.1 to 1% w / w, based on polar cosolvent propellants such as ethanol.

Optionally, the aerosol formulations according to the invention may further comprise one or more surfactants. The surfactant should be physiologically acceptable when administered by inhalation. Surfactants in this category include oleic acid, sorbitan trioleate, sorbitan mono-oleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan monool Latex, natural lecithin, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymer of oxyethylene and oxypropylene, synthetic lecithin, di Ethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, polyethylene glycol 400 , Cetyl pyridinium chloride, benzalkonium chloride, olive oil, glyceryl monolaurate, corn oil, cottonseed oil, sunflower seed Oils and the like. Suitable surfactants are lecithin, oleic acid, sorbitan trioleate. Suitable amounts of surfactant used range from 0.0001% to 50% w / w ratio, in particular from 0.05 to 5% w / w ratio, relative to drug.

Optionally, the aerosol composition according to the present invention may further comprise one or more stabilizers. Glycine, glycine, alanine, valine, leucine, isoleucine, methionine, threonine, isoline, phenylalanine, tyrosine, serine, histidine, tryptophan, proline, hydroxyproline, arginine, ornithine, aspartic Razine, Citrulline, Aspartic Acid, Cysteine, Glutamic Acid, Glutamine, Lysine, Hydroxylysine, N-acetyl-L-Cysteine, Phenylalanine, Trans-4-hydroxy-L-Proline, Tyrosine, L-Aspartatyl-L- Stabilizers can be selected from the group consisting of phenylalanine methyl esters, and any mixtures thereof.

Optionally, the aerosol composition of the present invention may also further comprise one or more antioxidants. Anti-oxidants can be selected from the group consisting of tocopherol, deteroxime mesylate, methyl paraben, ethyl paraben, ascorbic acid and mixtures thereof. Suitable anti-oxidants are tocopherols.

Packing

According to one embodiment of the invention as can be seen in FIG. 6, the drug consists of an impermeable or substantially impermeable soft packaging 10, in which the predetermined dose of the pressurized vessel 20, the suction device. 30, the molecular sieve 40 embedded in the sachet 50 is sealed in the internal volume 60.

Soft packaging is conventional and methods of making it are known to those skilled in the art. In general, the packaging material is made from flat reels of collapsible laminates and otherwise packed according to the packaging technique using sealing and cutting means. In this embodiment, the package can be made of a soft material of flat reel that can be rolled into a long tube and heat 14 welded to both edges of the tube. Cross seal 12 using a straighter heater bar that secures the laminate tube before and after the package contents (aspirator and adsorbent sachet). The continuous tube is cut into individual packs. This treatment results in a long continuous seal 14 at the bottom half of the pack and a cross seal 12 at both ends.

Other packaging types may include one or more seals, depending on the desired container shape, for example flat seals, pleats or padded reinforcement plates. Sealing can be made using heat (welding) or pressure sensitive materials. In another embodiment, the soft laminate is sealed by applying heat or pressure, or by applying a vacuum to the bubbles or pouches containing the product and then sealing by applying heat.

While soft packaging is preferred, other types of enclosures or containers may also be used as appropriate, provided the selected enclosures are opaque to block water ingress, whether soft or not. Generally, when the packaging or enclosure is impermeable or substantially impermeable to moisture, it is impermeable or substantially impermeable to propellants that gradually leak out from the embedded pressure vessel. In such cases, the pressure in the package or enclosure will gradually increase, which is undesirable. As used herein, "substantially opaque" means that the amount of propellant is raised in the absence of means such as HFA absorbent material inclusions that can reduce the propellant in the inclusion or in the intrinsic volume of the package. . Or in other words, the rate of discharge of the propellant gas permitted by the package or enclosure is lower than the rate of introduction of the propellant gas discharged from the pressure vessel into the interior volume of the package or enclosure. Suitably, in the present invention, HFA p227 can pass substantially impermeable packaging materials in an amount corresponding to or less than about HFAp227 0.25 cc per square meter of packaging per day at about 1 bar air pressure and about room temperature, and For example, HFA 134a may pass substantially impermeable packaging in amounts equivalent to or less than about 4.1 cc of HFA 134a per square meter of packaging per day at about 1 bar atmosphere and at room temperature. In addition, the term "impermeable" for the propellant in this context means that the HFA propellant gas used in the present invention cannot pass through.

Soft materials to make packaging materials

Other materials may be used for the packaging, but the flexible material of the packaging is laminate. The biggest constraint is that the packaging material must be impermeable to moisture in the atmosphere and impermeable or substantially impermeable to the HFS propellant used.

Laminates used to make packages are generally co-extruded or glued together several layers of material to create a single layer of "laminate" in appearance. For example, a suitable laminate has three (3) layers bonded to each other: an inner layer, a barrier layer, an outer layer. For example, Pharmaflex Ltd. (an affiliate of Alcan Inc. (Cramlington, Northumberland, England)) has three layers: 12 micron polyester / 9 micron aluminum foil / 50 micron polyethylene (product catalog LMP-F BRI / 72 / H1). The laminated laminate film. In addition, another laminate that may be used in the present invention is polyester (16.9 g / 12 micron, oriented, acrylic coated) / low density polyethylene (20 g, tinted white with titanium dioxide) / aluminum foil (24.3 g / 9 micron) / polyethylene copolymer (5 g) / low density polyethylene (13 g) / linear low density polyethylene (37 g / 40 micron).

The inner layer is formed on the inner surface of the package (the part in contact with the inhaler device), usually becoming a thermoplastic layer and a heat-sealing layer. The material used for the inner layer may also be polyethylene or other polyolefin or cyclo-olefin material. In addition, certain materials, such as ionomers, are also used to make the inner layers. Inomers are sold under the trade name Surlyn. These inomer resins are distinguished from other polyolefin heat-sealed polymers by being very transparent, high impact resistance, low lamination haze, friction resistance, tear resistance, solid state toughness and moisture fire. It is permeable.

There is a barrier layer disposed between the inner and outer layers (sandwiched between the inner and outer layers), which provides the pack impermeable or substantially impermeable. Other metal materials that can be laminated to the barrier layer may also be used, but aluminum foil is commercially available. The general thickness of the aluminum foil layer is about 8 or 9 microns. Alternatively, metallized barrier layers may be made using tin, iron, zinc, magnesium or other metals coated by vacuum deposition or metals sprayed on polymer sheets.

The outer layer is located on the surface of the barrier layer, which is the opposite side of the inner layer, and this outer layer provides support, impact resistance and barrier layer protection, and makes the pack rigid. Although other materials such as paper are used, it is polyester that is commonly used as the material for the outer layer.

Adhesives may also be used to bond the layers of material together. The thickness of the adhesive layer is substantially thinner compared to the thickness of the substrate, heat seal or protective layer bonded to each other.

The number, size and shape of the layers is not limited to the layers shown in the drawings. If the flexible packaging material is impermeable or substantially impermeable to any HFA leakage from the MDI device and substantially prevents the ingress of water vapor or particulates in the intrinsic volume, it can be made of any number of layers of any size and predetermined thickness. have. The layer size, shape and number of layers of the packaging material are generally a function of the size and contents of the pressure vessel containing the drug and the HFA propellant.

Typical thicknesses suitable in the case of three layers have an outer layer of 1 to 40 microns, suitably 4 to 30 microns, more preferably 10 to 23 microns, most preferably 12 microns; The barrier layer is 1 to 100, suitably 3 to 70 microns, more preferably 5 to 50 microns, 6 to 20 microns, most preferably 9 microns. In the case of the inner layer a suitable thickness is 1 to 100 microns, suitably 5 to 70 microns, more preferably 10 to 60 microns, more preferably 20 to 55 microns and most preferably 50 microns.

Suitable embodiments include 12 to 23 microns thick polyester film as the outer layer. The polyester film is laminated to aluminum foil as a substrate layer 6 to 20 microns thick. The aluminum foil is laminated to an inner layer, such as a 20-50 micron thick polyethylene film.

Another suitable embodiment includes an aluminum metallized polyester film laminated to the inner layer described above. Yet another embodiment includes a polyester film coated with silicon oxide as described above. In yet another embodiment, a 12 to 30 micron thick polyester film outer layer is laminated to a 6 to 20 micron thick aluminum foil substrate layer, and as described above, a 12 to 30 micron thick foil in aluminum is an inner layer. It is laminated | stacked on the polyester film laminated | stacked on. In another embodiment, the 15-30 micron thick polypropylene film outer layer is laminated to a 6-20 micron thick aluminum foil barrier layer, as described above, the aluminum foil is laminated to the inner layer. Lamination of the present invention is laminated with an adhesive or extrusion laminated.

The laminate can be made to any thickness described above as long as the final laminate is made to be opaque or substantially opaque to HFA 134a or HFA p227.

Various techniques known to those skilled in the art can be used to test the permeability or substantially impermeability of the laminate. For example, three pieces of 75 mm diameter disks are stamped into the mold using the lamination material. Measure and record the thickness of the laminate. The sample is then placed in a laboratory and subjected to vacuum for at least 3 hours to bring it to 23 ° C. Once the overall vacuum is stable, approximately 50 psi HFA p227 propellant is provided to the top half of the disc sample, which is the discharge pressure of the cylinder at laboratory temperature, and the bottom of the cylinder is still in vacuum. A similar experiment can be run by feeding a 30 psi HFA 134a propellant to the top half of the disk sample.

HFA Adsorbents and Gases

As referred to herein, the "HFA adsorbent" has the ability to retain or compress HFA molecules on the surface of the material or in the internal structure, and such activity is referred to as "adsorption" or "absorption". Examples of such HFA adsorbent materials include molecular sieves, activated clays (montmorillonite, bentonite clay and other known active clays such as those supplied by ColinStewart Minchem Ltd., Cheshire, UK), activated alumina, silica, Zeolite, bauxite and mixtures thereof and the like.

The present invention is not limited to any particular HFA adsorbent or specific gaseous material. Although there are many HFA adsorbents and various propellant gas components, it is contemplated that properly selected HFA adsorbents can primarily capture most of the propellant gas components. Based on the information disclosed herein, those skilled in the art will be able to select an appropriate HFA adsorbent for a given propellant gas component. Practitioners can make initial selections based on their knowledge and experience (e.g., by determining factors such as molecular size of gas components, pore size of HFA adsorbents, charges they have, etc.), and as described here Or some other method) to determine the actual effect of the selected HFA adsorbent on a given propellant gas component. This test process needs to be repeated until a suitable HFA adsorbent is found.

As mentioned above, the most effective HFA adsorbent found by the applicant is a molecular sieve having a pore size of about 10 Angstroms. For example, the sachet of approximately 4 grams of molecular sieve supplied by AtoFina (Solihull, England) to Siliporite ^® may be sufficient to prevent expansion. For more information on molecular sieves or other uses that may be used in industry, see the Hajdu paper: Molecular Seives: Unique Moisture and Odor-Taste Control Material, D. Hajdu, TJ Dangieri and SR Dunne, TAPPIPolym., Laminations Coat . Conf. (1999), Vol. 2, p. Available at 655-662.

HFA Adsorbent Sachet

Sachets for incorporating HFA adsorbents in packages are not necessary but useful. HFA adsorbent sachets are available from many suppliers, including Sud-Chemie (Middlewich, England). Sachets in the form of "tea-bag" are generally made using polyamide or polyester fibers or mixtures thereof. Commercially available materials that can be suitably used to make the HFA adsorbent sachet are GDT-II (San-ei Corporation, Osaka, Japan), Tyvek (Perfecseal, Londonderry N. Ireland UK). However, it may be made of other convenient shapes or appearances, and may also be made of other permeable materials. Molecular sieves contained in commercially available sachets are available from several manufacturers. For example, AtoFina (Solihull, England) is commercially available under the trade name Siliporite ^® molecular sieve.

Pressurized vessel

As a pressurized container, an MDI container is preferable. The term "MDI" or "measurement dose inhaler" is a unit consisting of a can and a device for measuring a drug. Typical pressurized vessels that can be used as MDI are described, for example, in WO 96/32151, WO 96/32345, WO 96/32150, WO 96/32099, US Pat. Nos. 6,293,279, 6,253,762, 6,149,892.

The most common MDI cans and caps are made of aluminum or other metals and aluminum alloys, which may use other metals that do not affect drug formulation, such as stainless steel, copper or tin plates. MDI cans may be made of glass or plastic. However, the MDI cans used in the present invention are made of aluminum or alloys thereof. Advantageously, a reinforced aluminum or aluminum alloy MDI can may be used. Such reinforced MDI cans can withstand the tough coating and curing conditions such as the significantly higher temperatures required for certain fluorocarbon polymers.

Reinforced MDI cans with reduced tendency to deform at high temperatures include substantially ellipsoidal bottoms (larger angles between the bottom and sidewalls of the cans) with increased side and bottom thicknesses than conventional standard hemispherical MDI cans. .

MDI cans of the present invention include MDI cans supplied from Presspart (Blackburn, Lancashire, U.K.) or Neotechnic (Clitheroe, Lancashire U.K). MDI cans generally have a neck diameter of 20 millimeters, but can have a neck of any suitable diameter, and the height can vary from 30 millimeters to 60 millimeters.

While the basic novel features of the invention, such as those used in certain embodiments, have been described, various changes, substitutions or omissions may be made in the described packaging forms and methods which can be readily implemented by those skilled in the art without departing from the scope of the invention. It is enough. For example, it is also within the scope of the present invention to combine all of these elements and methods capable of carrying out the same functions in substantially the same way to achieve the same result.

The invention is not limited to the embodiments provided by way of example, but may be modified in various ways within the scope of the appended claims.

Claims (108)

(a) a pressurized MDI (metered dose inhaler) container comprising (i) a drug and an HFA propellant selected from the group consisting of HFA (hydroflooralkane) 134a and HFA p227 or mixtures thereof; ii) placing an effective amount of the HFA adsorbent material, which is 10 Angstroms molecular sieve, in a sealable package that is not permeable to the HFA propellant; (b) sealing the packaging to place the pressurized container and adsorbent in the interior volume of the packaging at a pressure equal to atmospheric pressure; And (c) absorbing any leaked HFA propellant by the HFA adsorbent material such that the intrinsic volume is maintained at atmospheric pressure, the method of packaging for a pressure vessel maintaining the intrinsic volume of the sealed packaging material at atmospheric pressure. The method of claim 1, wherein the molecular sieve absorbs about 230 ml of HFA p227 in an amount of about 4 g. The method of claim 1, wherein the molecular sieve absorbs about 230 ml of HFA 134a in an amount of about 4 g. The method of claim 1, wherein the packaging material is made of plastic. 5. The method of claim 4, wherein the plastic is a flexible laminate having a barrier layer that provides a package that is not permeable to HFA 134a and / or HFA p227. 6. The method of claim 5 wherein the soft laminate has three layers of polyester / aluminum / polyethylene, wherein the aluminum layer is located between the polyester layer and the polyethylene layer. 6. The method of claim 5 wherein the barrier layer is made of aluminum foil. (i) a pressurized MDI (measured dose of inhaler) container comprising a drug and an HFA propellant selected from the group consisting of HFA 134a and HFA p227 or mixtures thereof; (ii) an effective amount of HFA adsorbent material that is a 10 kPa (Angstrom) molecular sieve capable of absorbing the HFA propellant to maintain a constant pressure in the intrinsic volume in the event of any leakage of the HFA propellant from the pressurized vessel; And (iii) a packaged drug comprising an enclosed package having a pressurized container and an intrinsic volume in which the HFA adsorbent material is located, the HFA propellant cannot permeate, and the pressure in the enclosed volume of the packaging material equals atmospheric pressure. 9. The packaged drug of claim 8, wherein the drug is selected from the group consisting of bronchodilators, antihistamines, pulmonary surfactants, antiviral agents, corticosteroids, anti-inflammatory agents, anti-cholinergic agents, and antibiotics. 9. The package of Claim 8, wherein the pressurized MDI (measured dose of inhaler) container further comprises one or more excipients selected from the group consisting of surfactants, preservatives, fragrances, antioxidants, anticoagulants and cosolvents. medicine. The packaging drug of claim 8, wherein the HFA propellant is HFA 134a. The packaging drug of claim 8, wherein the HFA propellant is HFA p227. 10. The packaged pharmaceutical of claim 8 wherein the HFA adsorbent material is capable of absorbing HFA propellant up to about 25% of the adsorbent weight. The packaging drug of claim 8 wherein the HFA gas adsorbent material is capable of absorbing HFA propellant up to about 20% of the adsorbent weight. The packaging drug of claim 8, wherein the molecular sieve absorbs about 230 ml of HFA p227 in an amount of about 4 g. The packaging drug of claim 8, wherein the molecular sieve absorbs about 230 ml of HFA 134a in an amount of about 4 g. The packaging drug of claim 8, wherein the packaging material is impermeable to HFA 134a. The packaging drug of claim 8, wherein the packaging material is impermeable to HFA p227. The packaging drug of claim 8, wherein the packaging material is made of metal, glass or plastic and is selected from the group consisting of bottles, bags, drum boxes and irregularly shaped containers. 20. A packaged pharmaceutical product according to claim 19, wherein the packaging material is made of plastic. 21. The packaged pharmaceutical of claim 20 wherein the plastic is a soft laminate having a barrier layer that provides a package that is not permeable to HFA 134a and / or HFA p227. 22. The packaged pharmaceutical of claim 21 wherein the soft laminate has three layers of polyester / aluminum / polyethylene, wherein the aluminum layer is located between the polyester layer and the polyethylene layer. The package of claim 21, wherein the barrier layer is made of aluminum foil. The packaging drug according to claim 8, wherein the sealed packaging material is hermetically sealed by heat-sealing, gluing, welding, soldering, mechanical sealing or clamping, or pressing. The packaging material of claim 8, wherein the packaging material has a permeability of about 0.25 cc or less per square meter of packaging material per day at about 1 bar pressure and about room temperature for HFA p227, or about 4.1 per square meter of packaging material per day at about 1 bar pressure and about room temperature for HFA 134a. Packaging chemicals with permeability below cc and HFA adsorbent material being 10 Å (Angstrom) molecular sieve. The package of claim 25, wherein the molecular sieve absorbs about 230 ml of HFA p227 in an amount of about 4 g. 26. The packaged pharmaceutical of claim 25 wherein the molecular sieve absorbs about 230 ml of HFA 134a in an amount of about 4 g. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete

Images