SA00210204B1 - A small canister containing a combination of an active rectifier and a fluorohydrocarbon propellant - Google Patents

Abstract

Abstract: The present invention relates to a corrosion resistant stainless steel canister containing aerosol formulations containing a propellant gas with an active substance for use in inhalation therapy.

Description

A small canister containing a combination of an active rectifier and a propellant consisting of a fluorohydrocarbon Full description Scope of invention: The current invention relates to a small Alay of corrosion resistant stainless steel.

UST resistant stainless steel canister containing aerosol formulations containing propellant gas with an active substance for use in inhalation therapy The background of the invention in cpropellant-driven inhalers wld The active substances are stored with the propellant gas in small canisters, such as the cartridge-like canisters. These small canisters usually contain an aluminum container tightly closed by an aluminum valve cup in which a 96L8 valve is incorporated. Then a small 0 canister of this type can be placed in the inhaler as a cartridge 8 and may be left there permanently or replaced with a new cartridge after use. And given that chlorofluorocarbons (CFCs) chlorofluorocarbons have been forbidden to be used because of their harmful properties to the ozone layer, as mentioned at the Rio de Janeiro Conference in the early nineties »; Encourage the use of fluorohydrocarbons (FHC) ve as an alternative to use in propellant gas inhalers. The most sought-after examples to date are TG 1342 and TG 227 elu TTY OO) fluoropropane Ald dy -(1,1,1,2,3,3,3-heptafluoropropane) Cy peal systems had to be converted systems of delivery of existing systems used for inhalation treatment to CFC-free propellant gases o o r and the development of disposal systems and new formulations of the active substance. Surprisingly, aluminum cans containing fluorohydrocarbons (FHFCs) drug formulations act as propellant gases, but are highly susceptible to corrosion according to the formulation 005. This is especially true of formulations containing 0 materials. And in -free halides, specifically halides, 2-shot Aah lig ions and/or electrolytes corrosion, which indicates that it cannot be used as an aluminum material in these cases; aluminum is subjected to small cans. Similar instability has been observed In aluminum cans, casing material is packaged as fluorohydrocarbons gases when using aluminum fluorohydrocarbons such as acid or basic components (13) The formulations contained acidic or basic Ve components or in the form of additive substances. Additives cactive substances in the form of “flavor enhancers” surfactants, as well as “nexa-5” improvers, etc., antioxidants, anti-oxidation agents

J on a metered aerosol ging and a container made of stainless steel is known as a chlorofluorocarbon gas and contains chlorofluorocarbon electrolyte Ve

AO 740877 Propellant and Active Pharmaceutical Substance US Patent No. General Description of the Invention P One of the functions of the present invention is to provide a small package for propellant gas inhalers that is corrosion resistant in the presence of active substance compositions containing electrolytes As a fluorohydrocarbon gas, it is used for inhalation therapy and contains fluorohydrocarbon © Caffeine breaking strength and compressive strength Dasra 53 (compressive strength to withstand processing and use, which ensures the quality of the formulations stored in it and overcomes - Other known defects from the previous technology. An additional objective of the invention is to provide a small canister for use in inhalers

Jealie JS Talat 33_e 53La (pe eles (0S Cum nda Sli Jai ve) huh

¢ And amazingly; It is found that a canister consists of a vessel and a valve cavity with a valve wherein the receptacle is at least consisting of hy alloy of claim 1 and the canister or receptacle contains a composition of an active substance containing an electrolyte; It contains 1348 TG and/or 7. It solves Problem Ty of the invention. The alloy contains the following as constituents: chromium (Cr) nickel (Ni) molybdenum (Mo) iron (Fe) and carbon (C) The alloy may additionally contain on copper (Cu) manganese (Mn) 6 and silicon (Si) preferably in one of the alloys described below. The invention also relates to the use of a container or a small canister of this type consisting of a container and a valve cup with a valve in propellant-operated metered-dose aerosols J ( sla Inhalers and a process for their production. The invention will be described hereinafter in greater detail with reference to Figures 1 and 1. Brief Explanation of Drawings 0 Figure 1 : shows a small case consisting of eles ( ); valve cavity ( A ) and valve (4) in cross section. Figure 1 shows another embodiment of the valve cavity (A) and valve (9) in cross section. The small can (1) consists of a container (Y) to contain the pharmaceutical composition and a valve cavity (A). Figure 1 shows a small can (GE) (1) of the invention in cross section. 1) from a container (1) to contain the pharmaceutical composition and a valve cavity (8) with a valve (3) and the shape and dimensions of this small can correspond to the small aluminum canisters known from the previous technology. Yo and the container is (Y) According to the invention, it is made of an alloy containing: Meh

° iron fron at a rate ranging from LOY, mE, v nickel at a rate ranging from AYA YY, chromium at a rate ranging from 18.6- 77.0 molybdenum at a rate ranging from ,= 0.0 m > manganese pixie zero-77.0 copper copper 7.001 silicon zero-71.0 phosphorus ss With a ratio of zero-45, sulfur with a ratio of zero-9 is 70.87 and 0 carbon with a ratio of em jin 0.07 /1. This alloy is a hy alloy of article number 1.5074 from the Iron and Steel List of the Society of German Metallurgists. A preferred alloy of this type has the following composition: yo Chromium at a rate ranging from 171,190 nickel at a rate ranging from AYN, 0m 4.0 molybdenum at a rate ranging from 5.6 - .75 copper copper at a rate ranging from -7.0 0.1 manganese at a rate not exceeding 77.0 Y. Silicon at a rate not exceeding 0.50 7 and carbon at a rate not exceeding 70.07, provided that the ratio consists The remainder is mainly iron. For a similar substitute alloy (ly JE) the molybdenum content is limited to 4.5 -759.0¢0

+ The alloys mentioned above are sufficient to resist corrosion for various liquefied fluorohydrocarbons such as 1348 TG and 227 1 ( TG 1 1 7 Slaw FF fluoropropane 0 (1, 1,1, 2, 3) , 3, 3-heptafluoropropane These alloys contain propellant gas compositions with active substances suitable for inhalation therapy; surfactants; co-solvents; stabilizers; Jul so; OU are acids, bases or electrolytes; Jie hydroxide ions cyanide ions and/or halide anions such as fluoride, chloride, cchloride, bromide or .iodide The bowl (1) is formed from a shell made of one of the alloys described above. The bowl (1) has four different areas: J aud flat or concave, inwardly domed base (¥)«¢ a cylindrical portion (¢) incorporated into the tapering neck (©) of its upper third and finally ending in the convex end (1) which encloses the opening of the vessel ( 7). (A) Preferred embodiment The thickness of the vessel walls (1) ranges from 1 to 9 cals and the best ve is between yo 1.15 mm; the most preferred is between about 1.14 and ? mm. In a preferred embodiment The vessel (7) resists an Ay bursting pressure of Te (09 hPa; more than 000001 hPa is preferred; the most preferable is more than 08060608 hPa.. The weight of the vessel (Y) ranges in A preferred embodiment is between © and 9010 (ae) and the weight of the container (Y) is between 1 and 10 g in the cal embodiment The weight of the container is between AY, VA © g in a preferred embodiment as well. Equally, the size of the pan (7) ranges from © to 00 ml (l). Other Age Sly pans range from 10 to 100 ml while others range from about 11 to 10 ml. 08 ml In the closed state, the container (A) is closed tightly by means of the valve chamber (A) after it is filled with the pharmaceutical composition and propellant.

In the Al embodiment the valve bore (A) also contains a corrosion resistant material. One of the alloys described above is preferred for containers and/or plastic sala of suitable pharmaceutical quality. In another embodiment; The valve cavity (1) is made of aluminum and in this case mle forms the leakage (01) and/or valve (3) such that the valve cavity (A) itself does not come into contact with The liquid in the vessel. A preferred embodiment of the valve bore (A) is described in British Patent No. 7,774171 to which the entirety is referenced herein by reference. In the closed state of the small can, the valve bore (A) folds around the bowl (7) at its tip convex (6). Or disc in shape, preferably disc in shape, and may consist of materials known from previous technology, suitable for use in pharmaceutical formulations with fluorohydrocarbons as propellant gases, examples of suitable materials include thermoplastics, cthermoplasts, rubber polymers celastomers materials Jia neoprene yo 016001606 isobutylene isoprene butyl rubber cbutyl rubber buna rubber U sll nitrile rubber enitrile copolymers ethylene copolymers Propylene is terpolymers of ethylene, propylene, diene, Jia diene, butadiene, and fluorinated polymers. Preferred materials include ternary polymers of ethylene / propylene / diene. propylene/diene terpolymers (EPDM) 79 | : on the valve cavity (A) opposite the inside of the vessel; Form a valve (3) so that the (VY) valve stem passes through the valve cavity (A) to the other side. The valve (4) rests in the center hole of the gasket (01) to form a seal. The gasket ( V+) and valve (1) bas the valve bore (A) of the Jala seal the vessel so that it cannot come into contact vo with the liquid in the vessel (7).

A

The valve (3) is shaped so that each element capable of contacting the fluid within the vessel (7) is made of a material resistant to corrosion in relation to that fluid. Such elements protruding from (VY) include for example the spring or springs (11); the valve stem (VF) and the calibration chamber oA) in the valve bore (VY) inward-outward through the hole, preferably stainless steel (VY) and made of Spring (VE) and valve body 0 steel Other elements of the valve (9) may consist, for example, of stainless steel, (OF) (11) of the above-described alloy and/or plastic material. The most preferred poly-polyester elements consist of a plastic material; in particular the polyester (V €). polybutylene terephthalate.

OAT, as shown in Figure (1); Other gaskets may provide one or more Ve-sealing fluids to prevent liquid or gas from leaking from within one or more (V1) and/or (V0) ; Like gaskets, the bowl is outward. The gasket or gaskets may be located so that the liquid inside: the vessel comes into contact only with the vessel casing and valve; regardless of the actual gasket or gaskets. Optionally; Gul) to move ALE valve stem seal; which is (V0) and the gasket (VY) seals the valve stem (V1) and the gasket (A) controls its penetration into the valve cavity Vo and in this way; Prevent (VF) inside the valve relative to the valve body (£1) and/or metering chamber any liquid or gas from leaking from inside the vessel along the (V1) and (V0) outer stem gaskets The valve and the outside of the small enclosure or in contact with the valve bore are made of the same material as the gasket (10), preferably of the (V1) and (V0) method. The gaskets may be made of ethylene/propylene/diene terpolymer. of ethylene/propylene/diene 0 but aluminum of aluminium (A) the valve bore Cus and in one embodiment with the valve (01) shall not be made of one of the corrosion-resistant materials described above; it shall not The gasket completely isolates the valve cavity from the inside of the vessel. Therefore, in this case (9) (01) and valve (1) should not be in close contact with each other. There may be a gap between the gasket (01) and the gasket (01). directly on the underside (01) and the valve (4) and in such a case the gasket rests To

A

For (A) for example; It seals from the edge of the valve cavity (oA) to the valve cavity (A) in the valve cavity (VV) the hole (Vo) of the convex end (1) on the bowl. Then seal the gasket from the inside of the bowl tightly. with valve integrated into it (9). This is identical to (A) and another embodiment of the valve bore (01) is closely matched in Fig. 7. The main difference is that gasket 1 is the embodiment shown in Fig. > 1 In the embodiment shown in Fig. ¥ (18) they fuse to form a single gasket (VT) and the gasket (16) surrounds the gasket (14) on the underside of the valve plate (18). They are arranged so that the valve body is fused within The gasket is inserted through the hole (19) which is located below the hole (VY) of the gasket. The valve stem passes in dimensions sufficient to seal the stem (19) and the hole (A) is directly in the valve cavity (VY) (VA ) and the sealing material of the gasket (A) for the valve bore (VY) valve 0 (01) is identical to that described above for the gasket of the invention by a process corresponding to the processes known from the prior technology Gay (Y) It produces a small container and the like, as the container is minted from a sheet of aluminum material to produce aluminum cans, the subject of the invention, or the corresponding alloy. A: The receptacle (7) or the small box consisting of the receptacle (7) and the valve cavity ve with the valve (9) is suitable for use with propellant gaseous compositions containing compounds (8) and propellant gaseous compositions that can contain fluorohydrocarbons are described. Fluorohydrocarbons used in conjunction with the invention in IPC 177757/15 preferably acid propellant gaseous formulations 5040 containing 1348 26 and/or 1, 1, 1, 2, 3, 3, 3,-heptafluoropropane NFC Tect *- Heptafluoropropane 7 as a buffer gas, especially those containing ipatropium bromide (TG 227) “albuterol” oxitropium bromide ¢ipatropium bromide as an active substance. fenoterol or Fenoterol tiotropium bromide contains tiotropium bromide on the active substance; inorganic or organic acids may be used Tel inorganic acids;

Others: mineral acids and mineral acids, halic acids, in addition to halogen acids, nitric acid, hydrochloric acid, sulfuric acid, sulfuric acid, while examples of organic acids include phosphoric acid or nitric phosphoric acid. acid In the case of the presence of citric acid salts or ascorbic acid, ascorbic acid, therefore, in the Glas anion salt, these are the preferred acids, where the anion is (Aad) Substances in general for all active substances Wide citric acid The active substance. And it is citric acid and its salts, and it is also the most preferred. From 1 to 7, that the pH of the composition ranges from DS, and the acid content is preferably from * to ©, and it is better to be about 5, ?. In the case of inorganic acids, it is standard. In the case of 1501, the preferred acid content is in the range from about 07 to Ve. The preferred content is approximately in the range from ascorbic acid. Ascorbic acid is in the range from citric acid to © mg / ml. In the case of citric acid 08 to LR/NO? 4 mg/mL as the contributing solvent ethanol and formulations may additionally contain ethanol by weight from the formulation .75 0 to 1 *#hh#. The preferred amount ranges from 000 Some of the preferred eg formulations are the following formulations that can be stored in a small can or container of the type described above: 1 g ipatropium bromide monohydrate 77.9000 wt.

Ipatropium bromide monohydrate wt. 700-161 exchange ethanol ethanol wt. 745, 0 TG 134a

I inorganic acid by weight 75, = sia water huh

1

good?

Ipatropium bromide monohydrate AY, ema ey by weight

Ipatropium bromide monohydrate

Pure ethanol 6-20 by weight

0 TG 134a 744.09 wt

Ascorbic acid 9.58 mg / ml

Zo, sua purified water by weight

rg

Ipatropium bromide monohydrate 7.107 wt

Ipatropium bromide monohydrate

Ethanol 18 by weight

2,70 | TG 134a wt

Citric acid 68 by weight

Purified water 8 by weight

Total 0 wt

Ipatropium bromide monohydrate 4 2 wt Ipatropium bromide monohydrate ethanol pure 218 wt TG 134a 7 wt citric acid 68 wt 0 sla purified 8 wt total 0 wt °

hh

VY

> gid Ipatropium bromide monohydrate 2.074 by weight

Ipatropium bromide monohydrate 28 wt. ethanol 17 wt.: | TG 134a wt 78 citric acid citric acid wt 00 purified water total 28 wt + ga wt 70,197 Fenoterol hydrobromide 27.06 wt ethanol J si) wt 7 | TG 134a wt 7 citric acid purified water 5 wt wt 0 gross The method of filling small cans may be with the corresponding composition; For example, a method: a dual stage pressure fill method (eda) or a single stage cold fill method. single stage pressure fill method Huh

Claims (1)

VY active substance formulation containing an active substance formulation (1) canister small canister -1 \ TG134a with electrolyte or electrolyte base “acid walt” containing salt Y For use in inhalation therapy propellent gas as a propellant gas TG 7 and/or the cavity (1) container of a canister The small canister consists of cinhalation therapy ¢ The vessel is made of ad (3 ) valve so that the valve incorporates (A) valve cup of the valve ° nickel Tekel «/O¥, = f 4.0, with a ratio ranging from iron containing alloy 1 JF, with a ratio of Ranging from chromium chromium AYA TY 0 with a percentage ranging from v with a manganese percentage with a percentage ranging from +,%= 0,0 /¢ Manganese molybdenum A silicon Silicon 7.0-0.0 77.0 copper with a ratio of zero-4 with a ratio of zero- phosphorus J), 0 ja with a ratio of 1 with carbon and carbon A, YO Jha with a percentage of sulfur; Sulfur 8 11 Seton ranging from zero 0" consisting of container according to protection element 0; distinguished in that the canister is a small canister - 1 with a ratio ranging from 271.0-149.0 nickel chromium With the following composition: chromium alloy Y with a molybdenum tooth rate; Molybdenum AYN, 6-7 5.0% nickel 1% and no manganese manganese 7,001.00% Analy copper fo, —g, ¢ no carbon and carbon L090 with a percentage not exceeding 77.0 silicon, mainly fron, provided that the remaining rectifier consists of iron LY of more than 1. It is characterized by having a cavity oY to 1 according to which of the two protection elements from the canister? V¢ container Jalal for (YA) and/or v is distinguished in that the valve oF to 1 for any of the Gy canister protection elements; ?- small can 1 one or (11) stainless steel springs contains a stainless steel spring (9) valve Y and a body (VY) metering chamber ¢ (VY) valve stem more ¢ valve stem v % chamber 1 VY ) valve stem B Cray: 1 V¢ ) valve body is made of steel ()£) valve body s/s (1) metering chamber Calibration ° to? and/or of plastic 1 according to any of the elements of protection from alloy esteel 1 -plastic for it is distinguished in that the spring of according to any of the elements of protection from 3 to canister small box 5 1 stainless steel consisting (consisting) of stainless steel (11) Y spring(s) and the valve body (1 ¥) metering chamber; Calibration chamber (VY) valve stem 3 polybutylene terephthalate (PTFE) (10) valve body ¢ to © is distinguished in that 1 stem of any of the protection elements (ad, canister) Small 5 1 gasket with a gasket (1) A) valve cup sealing from the valve cavity (OY ) valve stem Y (YA) or (Ye) v in that the gasket eV to 1 For any of the elements of protection from Gy canister a small box 7-1 consisting of a polymer (VA) gasket and/or gasket “Tadaa (09) and/or gasket (01) # 1 . ethylene Tri-ethylene/diene/diene /propylene/diene to A is distinguished in that cavity 1 according to any of the canister protection elements Small box —A 1 - (1) container consisting of the same alloy as the container (A) valve cup Y ogo Yo is distinguished in that container A to 1 of any of the protection elements from a small Gig canister Ble 4 - 1 hPa 70001 exceeds the bursting pressure that bears the pressure of container Y of hPa. 000001, preferably more than v to 8. It is distinguished in that the container 1 for any of the protection elements is from a small Gy canister Ade -01 1 hPa. container Y is distinguished in that 0 to 1 for any of the protection elements from Gi canister small ale -11 / mm; v0 to 1.1 ranging from wall thickness container 7 mm Yo to 1.06 preferably from v is distinguished in that 00 to 1 according to any of the protection elements of a small canister de -1 1 mm .0 to 0.0 eV ranging from wall thickness container Y to 1; It is distinguished in that the degree of 1 according to any of the elements of protection from the canister is a small can — VY 1.5, 0 to Y,0 ranging from formulation, pH, acidity, Y. It is distinguished in that OY to 1 according to any of the canister protections Small box =) 1 contains active substance formulation Y hydroxide dons cyanide hydroxide dons choose from electrolytes 1 .halide anions and/or halide ions cyanide ions ¢ are distinguished in that the electrolytic materials VY ¢ of the protection element (as canister small can Yo 1 mah) 7 85 choose from fluoride ¢fluoride Chloride chelated; bromide or iodide iodide r salt contains salt active substance contains active substance composition container container =) 1 7 acid: base or electrolyte with 1348 TG and/or 227 TG as And propellant gas for use in cinhalation therapy is distinguished ¢ In that the container is made of an alloy according to which of Claims 1 and ?. 1-1 container according to the OT protection element is distinguished in that the container bears pressure 7 Bursting pressure of more than 700,010 hPa, preferably more than 7 hPa. YA \ - container according to protection element M1 is distinguished in that the container bears pressure 7 Bursting pressure of more than 1,000,000 hPa. 1 8- A container according to any of the protection elements from 11 to YA is distinguished in that the container container Y has a wall thickness ranging from 0.1 to 169 mm; Preferably from Ye v to Yo mm. } 0-1 container according to any of the elements of protection from 11 to OA is distinguished in that container 1 has a wall thickness ranging from 714 to 0.0 mm. -71 1 small canister canister according to any of the protection elements from 5 to yo characterized in pH y formulation ranging from 0 SY ,5. Meh No -'1 1 container according to any of the protection elements from vi to 11 is distinguished in that the composition of electrolytes containing active substance formulation Y 7 Choose from among hydroxide ions cyanide ions and/or ‘halide anions’ ¢ Electrolytes are distinguished in that the electrolytes YY according to the element of protection container 7 container 1 iodide bromide chloride chloride efluoride choose from fluoride Y .iodide and container sles to 10 or 1 depending on the canister protections ?- use for 1 small canister and/or storage of the inhaler in a YY inhaler to 11 for any of the Gi Y A protections Madd) is distinguished in that the composition of the substance is cactive substance formulation ¥ cosolvent formulations aS ethanol containing ethanol active substance formulation ¢ “oxitropium bromide” cipatropium bromide and ipatropium bromide fenoterol or fenoterol albuterol ctiotropium bromide 1 .active substance 7 —Yo 1 use of a small canister of claim 4; It is distinguished in that the composition of the active substance Y contains ethanol Js and cipatropium bromide 1 bromide of oxitropium bromide or tiotropium bromide ¢ as an active substance YT Gi's use of the protective element YE or YO is distinguished in that the formulation Y contains an annulable acid. 0 cto YA formulation is distinguished in that the composition Yo or YE of the protective element Gy the use of 1 —YY mineral acid .YY contains a mineral acid Y that is distinguished in that the formulation contains acid (YO for the protection element ?or Gay use 1-78 “hydrochloric acid 1 0¢o