US3809294A - Dispensing lung contacting powdered medicaments - Google Patents

Dispensing lung contacting powdered medicaments Download PDF

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Publication number
US3809294A
US3809294A US00374176A US37417673A US3809294A US 3809294 A US3809294 A US 3809294A US 00374176 A US00374176 A US 00374176A US 37417673 A US37417673 A US 37417673A US 3809294 A US3809294 A US 3809294A
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United States
Prior art keywords
container
aerosol
button
mouthpiece
holder
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Expired - Lifetime
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US00374176A
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English (en)
Inventor
W Torgeson
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Wyeth Holdings LLC
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American Cyanamid Co
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Application filed by American Cyanamid Co filed Critical American Cyanamid Co
Priority to US00374176A priority Critical patent/US3809294A/en
Priority to CA194,459A priority patent/CA1043208A/en
Priority to ZA00741633A priority patent/ZA741633B/xx
Priority to IL44401A priority patent/IL44401A/en
Priority to AU66762/74A priority patent/AU484817B2/en
Priority to IE574/74A priority patent/IE40616B1/xx
Priority to GB1270674A priority patent/GB1471917A/en
Priority to PH15648A priority patent/PH11643A/en
Priority to AR253017A priority patent/AR198562A1/es
Priority to DE2415360A priority patent/DE2415360C2/de
Priority to IT49957/74A priority patent/IT1003994B/it
Priority to NLAANVRAGE7404626,A priority patent/NL178655C/xx
Priority to DD177768A priority patent/DD125188A5/xx
Priority to SU2017264A priority patent/SU537614A3/ru
Priority to YU00989/74A priority patent/YU36435B/xx
Priority to BE143026A priority patent/BE813512A/xx
Priority to AT299974A priority patent/AT342211B/de
Priority to FR7412670A priority patent/FR2234905B1/fr
Priority to JP49041581A priority patent/JPS6010737B2/ja
Priority to SE7405022A priority patent/SE405448B/xx
Priority to CH555174A priority patent/CH577832A5/xx
Application granted granted Critical
Publication of US3809294A publication Critical patent/US3809294A/en
Priority to PL1974172163A priority patent/PL89980B1/pl
Priority to DK343874A priority patent/DK152967C/da
Priority to ES427755A priority patent/ES427755A1/es
Priority to CS7400004539A priority patent/CS182257B2/cs
Priority to CH1325075A priority patent/CH620207A5/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0086—Inhalation chambers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/06—Solids
    • A61M2202/064—Powder

Definitions

  • ABSTRACT A combination aerosol container carrier and deceleration chamber carries an aerosol container in one configuration and in another dispenses powdered medicament from the aerosol container with inhaled particles predominantly below 10 microns in size at a low velocity which gives a comparatively high degree of topical effect in the lungs as compared with systemic effeet from powders .absorbed in the mouth.
  • the lungs may be used as an effective administration route for systemic medicament effect.
  • the present invention is based upon the discovery that the discharge from an aerosol container can be suspended in dry vaporized propellant mixed with air by theme of a deceleration chamber which is big enough to serve as a carrier for the aerosol container in a storage and transportation configuration and which has a neckeddown mouthpiece at one end and a neckeddown spray system at the other.
  • the deceleration chamber is about the same volume as the human oral cavity, with the mouth open. It serves to decelerate the aerosol charge to give a' low velocity to the dispersed powder, absorb the aerosol jet momentum before the suspended powder enters the users mouth, complete the vaporization of the aerosol propellant, eliminating the possibility of liquid propellant reaching the mouth, dilute, the propellant and suspended powder with air, and give uniform and acceptable powder losses, so that uniform doses are administered. It is desirable that a major portion of a discharged medicament be administered to the user, but it is more important that each dose be of consistent and predictable size and absorbability so that a known uniform dose is administered with each actuation of the actuation button. A considerable percentage of loss is acceptable if reliably uniform.
  • the deceleration chamber traps much of the medicament that would deposit in the mouth of the user, so that a relatively small amount of the medicament is deposited in the mouth as compared to the amount that reaches the lungs, and is effective in the lungs.
  • a trap system is used to submerge the metering valve to insure that the metering valve is immersed in the propellant at all times so that the metering chamber does not drain and, in efiect, lose its prime. This at times is'referred to as a drain-free trap.
  • the system is. particularly adapted to the use of such drugs as triamcinolone acetonide and N,N-diethyl-4- methyl-l-piperazine carboxamide pamoate(diethylcarbamazine pamoate), both of which are of value in the treatment of asthma and both of which are desirably administered in small known uniform accurate dosages which are absorbed primarily in the lung system as con- 2 trasted with the nose and throat.
  • the physiological effectiveness is augmented by the possibility of increasing the concentration of drugs administered to the desired location, as compared to that obtained when the drugs are administered systemically.
  • Some medicaments are conveniently administered by inhalation, for a systemic effect.
  • Penicillin has been administered by inhalation,'as more convenient than by injection.
  • Many drugs are absorbed through the lugs, if a suitable system of dispensing for inhalation is available.
  • the inhalation of gases, such as ether, or liquids is much more common.
  • valves may be used for metering doses for the present invention.
  • U. S. Pat. No. 3,219,533, Mullins, Nov. 23, 1965, Aerosol Solid Medicament In Propellant And Low- Level Ethanol Avoiding Higher-Level Ethanol Dis Aerosol Apparatus shows an aerosol liquid dispenser using coaxial concentric extendable tubes for particle size control.
  • the tubes in collapsed position function as a container carrier for storage.
  • the mass of air in the tubes impedes the forward flow of a spray and serves as a partial barrier to the discharge jet.
  • the inside diameter is preferably 18 to 30 mm. and the length 3 to 10 times the diameter, preferably 5 to 7 times.
  • the aerosol container and valve are taken out of the stored position, and the valve stem is inserted into a dispensing spray head which forms the end of the inner tube at the time of use.
  • the particles of the therapeutic agent should be between 0.5 and microns in size, since particles above 5 microns may not reach the air-cells in the lungs while particles below 0.5 microns may fail to be deposited in the lungs.
  • Ramis teaches using dichloro-difluoro-methane as the propellant in which the active product is dissolved or kept in a homogeneous-emulsion suspension. The disclosures are limited to soluble products.
  • a dispensing package for therapeutic agents'under pressure such as shown in Meshberg, US. Pat. No. 3,012,555, supra, is modified by adapting a valve to dispense a powdered medicament suspended in the propellant and discharging the nozzle into the entrance of a decelerationchamber having a cylindrical barrel portion, a mouthpiece at the exit end, and container hOlder-tactuating button holder to hold the spray nozzle system.
  • the deceleration and expansion chamber is adapted to completely enclose and hold the aerosol container during storage with the system being assembled in one configuration for storage and transportation and another for use.
  • the assembly in storage and transportation position is protected from contaminating dust and may be conveniently carried in the pocket of a user and yet be rapidly assembled with minimum risk of contamination of the contents at the time of use.
  • FIG. 1 is a pictorial view of the aerosol dispenser assembled in dose administering configuration.
  • FIG. 2 is a view in partial section showing the dispenser in the storage and transportation configuration.
  • FIG. 3 is enlarged view in section showing the valve assembled to the expansion chamber cover and particularly, an anti-drain tank to insure that the metering valve is continuously immersed in the propellant and, thus, protected from partial draining and resulting irregular dosages.
  • FIG. 4 shows the same valve assembly in compressed position after a dose in which the valve stem has been depressed.
  • FIG. 5 is a second configurationin which the'actuating button fits into a movable applicator nozzle for storage.
  • the deceleration chamber preferably of a plastic such as polyethylene.
  • the deceleration chamber has a cylindrical barrel 12 which conveniently may be'about 2 94 inches in length and 1 A inches in internal diameter with a shell wall thickness of around one-sixteenth inch.
  • a mouthpiece 13 conveniently about seven-eighths inch in outside diameter economical method of manufacture and a smooth, easily cleanable working surface.
  • a mouthpiece cap 15 fits removably on the mouthpiece in dust excluding relationship. The cap may slide on either interiorly or exteriorly with a finger friction fit.
  • finger friction fit is used to note a frictional relationship which will hold pieces together under normalhandling conditions, but may be readily disengaged or engaged by finger pressure only.
  • the exterior-surface of the mouthpiece cap may be roughened or knurled for easier grasping by the fingers.
  • the edges of the mouthpiece cap and the mouthpiece may be broken" or slightly rounded in accordance with conventional practice for ease in assembly, as may other edges. Either the mouthpiece or the mouthpiece cap may have small ribs of the order of' 0.002 inch to reduce friction and ease engagement.
  • a container holder 16 At the open end of the cylindrical barrel 12 is a container holder 16.
  • the container holder' is a multifunctional element.
  • a holder flange 17 fits across the open end of the cylindrical barrel 12.
  • a positioning sleeve 18 engages the end of the cylindrical. barrel 12.
  • the positioning sleeve fits interiorly'of the cylindrical barrel 12 with a friction fit and the positioning sleeve is long enough to, prevent acv 5 cidental disengagement but permit ready removal of the container holder 16.
  • the positioning sleeve 18 extends from the holder flange 17 so that its resilience permits finger frictional engagement with the normal accuracy of molding parts.
  • a containerholding sleeve 19 extends interiorly from the holder flange l7 and is of a size to fit around, retain, and position an aerosol container 20.
  • the aerosol container 20 is of stainless steel or aluminum to hold high pressure aerosol propellants.
  • the container holding sleeve is long enough and of a size to position and retain the aerosol container assembly inside and axially of the deceleration chamber 11 during storage and transportation phases of using the device, and permits ready disengagement from the aerosol container 20 at the time of administration.
  • vents 21 Through the holder flange extend one or more-air vents 21 which provide for the introduction of diluent air during use. Three vents, each /8111Ch diameter, give good results. V
  • a button holder 22 Extending exteriorly from the holder flange 17 is a button holder 22.
  • the button holder is hollow, has a closed end opposite to the holder flange, and has therein an indexing port 23 which is of a size and shape to hold an aerosol actuating button 24, which is described in more detail below. Because the aerosol actuating button is to be oriented, the shape of the indexing port 23 is such as to match with the actuating button 24 and hold the actuating button in anoriented relationship.
  • the actuating button is cylindrical with a flat side 25 whichflat side cooperates with an indexing port flat 26 so that the spray is directed axially of the deceleration chamber.
  • the button holder is formed with two indexing ports 23 in diametrically opposed relationship so that the actuating button 24 can be inserted from either side and the other port serves such as an additional air inlet.
  • a retaining bead 27 which conveniently extends up about S/IOOOths of an inch above the exterior cylindrical surface of the button holder.
  • a protective sleeve 28 fits in light frictional engagement over and on the exterior surface of the button holder. Being made of plastic, there is sufficient resilience that the protective sleeve 28 may be easily forced over the retaining head 27 into position and is not readily removed so that it is retained in place during the useful life of the dispenser.
  • the protective sleeve has button apertures 29 to permit the sleeve 28 to be rotated so that the button apertures 29 index with the indexing ports and permit the button to be inserted therethrough and yet can be rotated through about 90 to protect the assembly from the entrance of dust and dirt during storage and transportation.
  • FIG. 2 is shown the dispenser in the carrying configuration for storage and transportation in which the container 20 is removed from the container holding sleeve 19, the protective sleeve 28rotated until the button apertures 29 index with the indexing port 23, and assembled in dose administering configuration by inserting the actuating button 24 through the button aperture 29 into one of the indexing ports 13 so that the spray port 32 is axial and concentric with the cylindrical barrel 12 of the deceleration chamber, so that the discharge from the aerosol container is symmetrical with respect to the deceleration chamber.
  • the aerosol container 20 extends upwards so that the medicament in propellant 33 is drawn by gravity against the valve assembly 30.
  • the actuating button '24 has a spray port 32.which is conveniently counterbored into the button and has a spray orifice 34 through which the medicament in propellant is discharged.
  • This spray orifice may either be formed integral with the spray button or a separate metallic insert may be used. Both are conventional constructions.
  • the spray orifice should have a diameter such that the discharged dose is disbursed in finely divided form as a cone on exit from the spray orifice.
  • An orifice of about 0.015 to 0.018 inch gives a good spray pattern.
  • the actuating button- 24 fits snugly on the end of a valve stem 35 which extends into the valve body 36.
  • the valve body 36 has therein a metering chamber 37 in which the valve stem 35 is slidably mounted.
  • a metering gasket 38 which performs the dual function of serving as a seal against loss of propellant when the valve stem collar 39 presses against the metering gasket, and acts as a ring seal around the valve stem 35 so that as the valve stem is depressed against the valve spring 40, the metering port 41 in the valve stem passes the metering gasketand permits the contents of the metering chamber to pass through the metering port 41, the axial valve stem bore 42, extending throughthe valve stem, into the discharge passage 43 in the actuating button'24 to the spray orifice 34.
  • valve stem 35 At the inner end of the valve stem 35 are charging flutes 44. These cooperate with a charging gasket 45 which is held against the lower end of the metering chamber by a stainless steel valve stem washer 46 which, in turn, isheld against the bottom of the metering chamber 37 by the valve spring 40. In operation, as the valve stem 35 is depressed, the
  • valve stem 35 passes through the charging gasket 45 so that the charging flutes pass through the charging gasket and the full diameter of the valve stem 35 sealsagainst the charging gasket 45 so that the metering chamber is filled and closed at the inner end before the metering port 41 passes the metering gasket 38 which permits the contents of the metering chamber to discharge through the.
  • metering port 41, the axial valve stem bore 42, the discharge passage 43, and the spray orifice 34 passes through the charging gasket 45 so that the charging flutes pass through the charging gasket and the full diameter of the valve stem 35 sealsagainst the charging gasket 45 so that the metering chamber is filled and closed at the inner end before the metering port 41 passes the metering gasket 38 which permits the contents of the metering chamber to discharge through the.
  • metering port 41, the axial valve stem bore 42, the discharge passage 43, and the spray orifice 34 are examples of the metering gasket 38 which permits the contents of the metering chamber to discharge through the.
  • FIG. 4 shows the actuating button 24 in depressed position with the valve in the discharge position.
  • valve stein 35 When pressure on the actuating button 24 is released, the valve stein 35 is pushed outwardly by the valve spring 40 so that the metering port 41 passes the metering gasket 38 which closes discharge from the metering chamber, and later the charging flutes 44 pass the charging gasket 45 permitting the propellant containing the medicament to flow through the charging flutes 44 and again fill the metering chamber 37.
  • valve body 36 a valve body flange 47 which covers the end of'the aerosol container 20 and is sealed thereto by a container gasket 48.
  • the ferrule 31 holds the assemblyin position against the end of the aerosol container 20 by the ferrule 31 being swaged against the stainless steel or aluminum aerosol container 20.
  • a metering valve is one type of metering valve.
  • Other conventional types of metering valves may be used.
  • the metering valve discharges a comparatively small charge; for instance about 50 microliters per actuation is a convenient commercial size, and each discharge has a volume of about that of a small drop of water, it is important that the metering chamber be completely filled before each actuation and that the metering chamber be prevented from draining back into the aerosol container between actuations.
  • This loss of charge or loss of prime is prevented by an anti-drain tank 49.
  • the anti-drain tank 49 fits into a flange sleeve 50 on the valve body flange 47 which flange sleeve 50 has an interior cylindrical surface against which the anti-drain tank 49 is asnug friction fit.
  • a charging'passageSl which provides for refilling of the anti-drain tank from the main body of the medicament in propellant in the aerosol container.
  • the anti-drain tank is sonically welded into position using an ultrasonic seal in which ultrasonic energy is passed through the flange sleeve to the anti-drain tank.
  • ultrasonic sealing By such ultrasonic sealing, the assembly is economical and effective. When so sealed, the anti-draintank remains in position under any use or abuse that does not damage the aerosol container itself.
  • the actuating button when the actuating button is depressed with the aerosol container in dispensing position, the contents of the metering chamber are discharged and as the actuating button is released, a new charge is drawn from the antidrain tank into themetering chamber and the antidrain tank is refilled through the charging passage 51.
  • the anti-drain tank remains filled with the propellant containing the medicament independent of the orientation of the aerosol container.
  • a predictable, uniform, accurate dosage is dispensed with each actuation of the actuating button.
  • the homogeneity of the solid finely divided medicament in the propellant is maintained more uniformly, and more consistent uniform doses are dispersed.
  • the use of a plstic anti-drain tank appears to aid in neutralizing electrical charges which would otherwise build up in the system.
  • the periphery of the propellant charge is effectively at a single potential, but the propellant can act as a dielectric so that the individual particles of medicament become charged and affect their dispersion and discharge-rate.
  • the effect of the stainless steel container is at least in part neutralized so that static effects are reduced or minimized permitting more uniform charge characteristics. 7
  • the first 25 percent of discharge doses are found to be higher than the last 25 percent so that the user is receiving more medi-, cation than anticipated from the new dispenser and less than anticipated from the nearly empty dispenser.
  • the variation in charges are minimized so that the user is obtaining a more reliably uniform dosage of the medicament.
  • any particles still retain velocity, they either impinge or are retained by the walls of the deceleration chamber or are bounced away from the walls so that a dispersed powder charge is formed which is mixed with additional diluent air and inhaled, as the user inhales the finely divided medicament through the mouthpiece.
  • the dosages are so small that about a 25 to 50 percent loss in the deceleration chamber is a highly acceptable loss as compared with the advantages of consistency and uniformity of the dose which is administered to the patient.
  • FIG. 5 is shown a modification of the aerosol dispenser system in which the container holding sleeve of the type shown in Meshberg, U.S. Pat..No. 3,012,555, supra, is used with an applicator nozzle 52 fitting in the holder flange 53 with the bottom end of the aerosol container fitting into the applicator nozzle.
  • Slidably fitting in the other end of the applicator nozzle is a button holding slide 54 which can be pressed inward for sealing or pulled'outward to hold the actuating button in operating position.
  • the details of this construction are shown in said U.S. Pat. No. 3,012,555.
  • deceleration chamber is large enough to decelerate the dispensed aerosol charge and permit the inhalation velocity from the inhalation of the user to be the sole factor in controlling the rate of administration at the time of use.
  • the energy of discharge is completely dissipated in the deceleration trap and a fine aerosol, almost a smoke, is formed of the drug to be administered, and this fine aerosol is inhaled into the lungs.
  • a smoke is normally defined as a suspension of fine solid particles in a gas such as may be produced by a fire with the particle sizes being in the colloidal range.
  • the particle sizes range from an overlap of the colloidal range at the small end to slightly larger than a true colloid.
  • the definitions as to particle size ranges are somewhat overlapping.
  • a particle size range from about 0.5 microns to microns gives good results. Particleslarger than about 10 microns are too apt to be deposited in the mouth or the throat of the user to be preferred for inhalation therapy. A few particles in this size range are usually not deleterious, but contribute disproportionately to systemic absorption rather than through the lungs.
  • the chamber sure propellant system is preferred.
  • Dichlorodifluoromethane (Freon l2) which has a pressure'of about 80 pounds per square inch absolute at room temperature gives good results.
  • a stainless steel or aluminum container is preferred for such pressures to avoid damage from breakage.
  • Glass containers, or plastic containers, or a plastic covered and protected glass container may be used, but these are more conventional at lower pressures, of theorder of 30 to 50 pounds per square inch gage.
  • a plastic valve stem is preferred to metal, as the plastic valve stem'is less subject to binding or sticking from powder being packed around it.
  • a small amount of a]- cohol about 1 to 10 percent, functionsas a lubricant to keep valve action reliable. Some medicament in propellant systems function reliably without a lubricant.
  • the size of the container and the size of the metering chamber can vary widely depending upon the dosage desired'for actuation, and the number of 'doses desired to be given to a patient for administration.
  • EXAMPLE II Diethylcarbamazine Pamoate From Pamoic Acid y filtered through diatomaceous earth. The cake' is washed with three 2 liter portions of methanol. The filtrate and washes are charged in a 100 gallon glass lined kettle, 21 liters of water added, and 10.9 liters (130 moles) of concentrated hydrochloric acid is added fairly rapidly. A bright yellow solid precipitates immediately. Stirring is continued at room temperature for l k hours. Free pamoic acid is recovered by filtration and washed with three 20 liter portions of water.
  • the cake is slurried with about 80 liters of water for 1 hour, solids filtered off, the solids washed with three 2 liter portions of water and then with three 4 liter portions of methanol. The solid is then dried for 2 days at 5055C.
  • the crude pamoic acid (11.8 Kg.) is dis- 1 solved in 61 liters of dimethylformamide at 85-90C. Two pounds of diatomaceous earth are added and the mixture is stirred for one-half hour before filtering,
  • the cake is washed with three 3 liter portions of dimethylformamide.
  • the filtrate is added to 70 liters of water in a 50 gallon glass lined kettle. An additional 20 liters of water is added and the resulting mixture is stirred for 1 12 hours while being cooled to below 25C.
  • the purified pamoic acid is filtered off, pressed dry and then washed with three 6 liter portions of water followed by three 4 liter portions of methanol.
  • the pamoic acid is dried to a constant weight of 10.8 Kg. 86 percent based on 95 percent real starting disodium salt).
  • a l0.l Kg. (25.8 moles) portion of diethylcarbamazine dihydrogen citrate is dissolved in 80 liters of water and the solution is filtered.
  • a 1.96 Kg. (49.0 moles) portion of sodium hydroxide is dissolved in 100 liters of water and 10.0 Kg. (25.8 moles) of purified pamoic acid, prepared as described in this example, is added.
  • the pamoic acid-sodium hydroxide mixture is stirred for one-half hour, -2 pounds of diatomaceous earth is added, stirring is continued for 1 hour and the mixture is clarified by filtration.
  • the filtrate is charged in a gallon glass lined kettle, stirred and the diethylcarbamazine citrate solution is added as rapidly as convenient. A very thick creamcolored precipitate forms immediately. Forty liters of water is added. After 1 hour of stirring thev mixture thins out considerably. Stirring is continued for l more hour.
  • the product is collected by filtration and washed with three 15 liter portions of water. The material is dried at 50-55C., and then micro-milled twice in a fluid energy mill to give 13.5 Kg. of product.
  • a 10.8 Kg. portion of this diethylcarbamazine pamoate is dissolved in a mixture of 25 liters of dimethylsulfoxide and-50 liters of methanol at 65C.
  • the hazy solution is filtered through diatomaceous earth and the cake is washed with three 4 liter portions of methanol.
  • the filtrate and washes are charged in a 50 gallon glass lined kettle and warmed to dissolve any separated material. Forty liters of methanol are added and the solution is chilled to and maintained at 0 (E4C. overnight.
  • the product is fil rified pamoic acid in 400 ml of acetone heated to 50C.
  • N, N-diethyl-4-methyl-l-piperazinecarboxamide pamoate was passed through a fluid energy pulverizing mill and micronized to 0.5 to 10 microns, with 90 percent by weight being in the range of l to 5 microns. 300 milligrams thereof in dry form where introduced into a 10 milliliter stainless steel container adapted to be fitted with an aerosol metering spray nozzle, and thereto was added 0.75 grams of anhydrous ethanol.
  • a metering valve was used which discharged 50 microliters of contents per actuation which gives 1.3 milligrams of N,N-diethyl-4-methyl-l-piperazinecarboxamide pamoate per actuation with 65 milligrams of dichlorofluoromethane and 3.25 milligrams of ethanol being simultaneously dispensed. These are volatile and become mixed with. enough air so as to have minimal or no physiological activity.
  • Triamcinolone acetonide Triamcinolone acetonide was micronized in a fluid energy mill until percent by weight was in the particle size range of l to 5 microns.
  • a 19 ml. stainless steel container had charged thereto 30 mg. of the micronized triamcinolone acetonide, 0.244 ml. of anhydrous ethanol and was cold filledwith 19.5 grams of dichlorodifluoromethane at 40C, evaporation serving to chill the container, and an excess being added to allow for evaporation.
  • the filled containers were closed with a metering valve, as above described, and sealed. Dispersion in the propellant is improved when the filled containers are immersed in an ultrasonic bath that transfers energy .from' the transducer to the contents of the aerosol container.
  • the components can be mixed, treated ultrasoni cally, and pressure filled.
  • Pressure f lling ' is more complex for small scale runs, but often preferred for large size runs, and saves loss of the propellant.
  • the valve needs to be specifically designed for such pressure fill.
  • Each actuation of the valve button delivers about 0.1 mg. of triamcinolone acetonide.
  • Five actuations four times a day gives a dosage of about 2 mg. of triamcinolone acetonide.
  • a systemic dose'for a patient is about 8 mg. The lower level and delivery to the preferred site is a major'advantage.
  • the patient should be instructed to actuate the button to release the medicament into the deceleration chamber, and to inhale so that only the inspired air imparts velocity to the particles being absorbed.
  • the patient should hold the inspired dose for a'few seconds to permit absorption on lung surfaces before exhaling. A minor amount of the medicament is exhaled.
  • propellant in the preceding example is dichlorodifluoromethane, other chlorofluoroalkanes and their mixtures may be used.
  • An aerosol dispenser for dispensing uniform dosages of a finely-divided powdered medicament suspended in a propellant at a low velocity in inhalable dry aerosol form in the particle size range of 0.5 to 10 microns, comprising a circular cylindrical container carrier and deceleration chamber consisting essentially of a cylindrical barrel, and, at one end thereof, a mouthpiece and a mouthpiece-to-chamber flare, the mouthpiece being adapted to fit into a human mouth, said mouthpiece being cylindrical, and positioned coaxial with the cylindrical barrel by said flare,
  • a mouthpiece cap adapted to removably engage and close the mouthpiece indust excluding relationship
  • a removable container holder adapted to close the deceleration chamber in essentially air tight relationship, comprising a holder flange, adapted to fit in sealing relationship with the cylindrical barrel of said chamber, a container holding sleeve effectively coaxial and integral with theholder flange and of a size to hold a circular the holder aerosol container with a friction-fit, and a button holder coaxial with the holder flange with means to hold an actuating button on an aerosol container in indexed relationship to discharge axially with the deceleration chamber, in dose administering position,
  • a circular cylindrical aerosol container having a 14 dose metering valve having thereon an actuating button, which button fits into said button holding a means in a dispensing configuration and which container fits interiorly of the cylindrical deceleration chamber in a storage configuration.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Containers And Packaging Bodies Having A Special Means To Remove Contents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US00374176A 1973-06-27 1973-06-27 Dispensing lung contacting powdered medicaments Expired - Lifetime US3809294A (en)

Priority Applications (26)

Application Number Priority Date Filing Date Title
US00374176A US3809294A (en) 1973-06-27 1973-06-27 Dispensing lung contacting powdered medicaments
CA194,459A CA1043208A (en) 1973-06-27 1974-03-08 Dispensing lung contacting powdered medicaments
IL44401A IL44401A (en) 1973-06-27 1974-03-12 Aerosol dispenser for inhalable powdered medicaments
ZA00741633A ZA741633B (en) 1973-06-27 1974-03-12 Dispensing lung contacting powdered medicaments
AU66762/74A AU484817B2 (en) 1973-06-27 1974-03-18 Dispensing lung contacting powdered medicaments
IE574/74A IE40616B1 (en) 1973-06-27 1974-03-19 Apparatus for dispensing dosages of powdered medicaments by inhalation
GB1270674A GB1471917A (en) 1973-06-27 1974-03-21 Apparatus for dispensing dosages of powdered medicaments by inhalation
PH15648A PH11643A (en) 1973-06-27 1974-03-21 Dispensing lung contacting powdered medicaments
AR253017A AR198562A1 (es) 1973-06-27 1974-03-28 Dispositivo suministrador de aerosol
DE2415360A DE2415360C2 (de) 1973-06-27 1974-03-29 Aerosolabgabevorrichtung zum Abgeben eines pulverförmigen Medikamentes in gleichförmigen Dosen
IT49957/74A IT1003994B (it) 1973-06-27 1974-04-02 Perfezionamento negli inalatori nebulizzatori
NLAANVRAGE7404626,A NL178655C (nl) 1973-06-27 1974-04-04 Aerosolafleverinrichting.
DD177768A DD125188A5 (de) 1973-06-27 1974-04-08
SU2017264A SU537614A3 (ru) 1973-06-27 1974-04-09 Дозатор аэрозол
YU00989/74A YU36435B (en) 1973-06-27 1974-04-09 Doser for medicaments in pulverized form
BE143026A BE813512A (fr) 1973-06-27 1974-04-09 Administration de medicaments de contact en poudre pour les poumons
AT299974A AT342211B (de) 1973-06-27 1974-04-10 Aerosolabgabevorrichtung
FR7412670A FR2234905B1 (de) 1973-06-27 1974-04-10
JP49041581A JPS6010737B2 (ja) 1973-06-27 1974-04-10 肺臓直達紛末医薬投与器
SE7405022A SE405448B (sv) 1973-06-27 1974-04-11 Aerosoldispenser
CH555174A CH577832A5 (de) 1973-06-27 1974-04-23
PL1974172163A PL89980B1 (de) 1973-06-27 1974-06-25
DK343874A DK152967C (da) 1973-06-27 1974-06-26 Inhalator til afgivelse af ensartede pulverdoser
ES427755A ES427755A1 (es) 1973-06-27 1974-06-27 Perfeccionamientos en suministradores de aerosoles.
CS7400004539A CS182257B2 (en) 1973-06-27 1974-06-27 Apparatus for application of aerosol powdered medicines into lungs
CH1325075A CH620207A5 (de) 1973-06-27 1975-10-13

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US (1) US3809294A (de)
JP (1) JPS6010737B2 (de)
AR (1) AR198562A1 (de)
AT (1) AT342211B (de)
BE (1) BE813512A (de)
CA (1) CA1043208A (de)
CH (2) CH577832A5 (de)
CS (1) CS182257B2 (de)
DD (1) DD125188A5 (de)
DE (1) DE2415360C2 (de)
DK (1) DK152967C (de)
ES (1) ES427755A1 (de)
FR (1) FR2234905B1 (de)
GB (1) GB1471917A (de)
IE (1) IE40616B1 (de)
IL (1) IL44401A (de)
IT (1) IT1003994B (de)
NL (1) NL178655C (de)
PH (1) PH11643A (de)
PL (1) PL89980B1 (de)
SE (1) SE405448B (de)
SU (1) SU537614A3 (de)
YU (1) YU36435B (de)
ZA (1) ZA741633B (de)

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US3994421A (en) * 1975-09-29 1976-11-30 American Cyanamid Company Unitary therapeutic aerosol dispenser
US3998226A (en) * 1975-09-22 1976-12-21 Edward G. Gomez Inhalation device for encapsulated concentrates
US4114615A (en) * 1975-12-12 1978-09-19 Aktiebolaget Draco Aerosol inhalation device
US5040527A (en) * 1990-12-18 1991-08-20 Healthscan Products Inc. Metered dose inhalation unit with slide means
US5074294A (en) * 1988-06-22 1991-12-24 Chiesi Farmaceutici S.P.A. Device for dispensing metered amounts of aerosol for inhalation
US5186164A (en) * 1991-03-15 1993-02-16 Puthalath Raghuprasad Mist inhaler
US5598836A (en) * 1995-05-26 1997-02-04 Healthscan Products, Inc. Metered dose inhalation unit with slide means
US5653962A (en) * 1991-12-12 1997-08-05 Glaxo Group Limited Aerosol formulations containing P134a and particulate medicaments
US5658549A (en) * 1991-12-12 1997-08-19 Glaxo Group Limited Aerosol formulations containing propellant 134a and fluticasone propionate
US5674471A (en) * 1991-12-12 1997-10-07 Glaxo Group Limited Aerosol formulations containing P134a and salbutamol
US5674472A (en) * 1991-12-12 1997-10-07 Glaxo Group Limited Canisters containing aerosol formulations containing P134a and fluticasone propionate
US5736124A (en) * 1991-12-12 1998-04-07 Glaxo Group Limited Aerosol formulations containing P134a and particulate medicament
US5744123A (en) * 1991-12-12 1998-04-28 Glaxo Group Limited Aerosol formulations containing P134a and particulate medicaments
US5817293A (en) * 1991-12-12 1998-10-06 Glaxo Group Limited Canister containing aerosol formulations containing P134a and particulate medicaments
US5839429A (en) * 1994-03-25 1998-11-24 Astra Aktiebolag Method and apparatus in connection with an inhaler
US5916540A (en) * 1994-10-24 1999-06-29 Glaxo Group Limited Aerosol formulations containing P134A and/or P227 and particulate medicament
US5922306A (en) * 1991-12-12 1999-07-13 Glaxo Group Limited Aerosol formulations containing P134a and particulate medicament
US5976573A (en) * 1996-07-03 1999-11-02 Rorer Pharmaceutical Products Inc. Aqueous-based pharmaceutical composition
US5993805A (en) * 1991-04-10 1999-11-30 Quadrant Healthcare (Uk) Limited Spray-dried microparticles and their use as therapeutic vehicles
US6293279B1 (en) 1997-09-26 2001-09-25 Trudell Medical International Aerosol medication delivery apparatus and system
US6345617B1 (en) 1997-09-26 2002-02-12 1263152 Ontario Inc. Aerosol medication delivery apparatus and system
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US6743413B1 (en) 1991-12-18 2004-06-01 3M Company Suspension aerosol formulations
US7101534B1 (en) 1991-12-18 2006-09-05 3M Innovative Properties Company Suspension aerosol formulations
US7105152B1 (en) 1991-12-18 2006-09-12 3M Innovative Properties Company Suspension aerosol formulations
US20070253913A1 (en) * 2003-09-10 2007-11-01 Nahed Mohsen Aerosol formulations for delivery of dihydroergotamine to the systemic circulation via pulmonary inhalation
US20080127971A1 (en) * 2004-09-13 2008-06-05 Michael King Dry Powder Inhalers that Inhibit Agglomeration, Related Devices and Methods
US20080287451A1 (en) * 2007-02-11 2008-11-20 Cook Robert O Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile
US20090090355A1 (en) * 2002-05-02 2009-04-09 Pari Innovative Manufacturers Aerosol medication inhalation system
US20100191252A1 (en) * 2004-10-15 2010-07-29 Laboratory Tickner B.V. Device for removing a tick
US20110171141A1 (en) * 2009-06-26 2011-07-14 Kellerman Donald J Administration of dihydroergotamine mesylate particles using a metered dose inhaler
US8080236B2 (en) 2002-04-17 2011-12-20 Nektar Therapeutics Uk, Ltd Particulate materials
USRE43174E1 (en) 2000-04-11 2012-02-14 Trudell Medical International Aerosol delivery apparatus
USD744636S1 (en) * 2013-02-14 2015-12-01 Clement Clarke International Limited Spacer for inhaler
USD748242S1 (en) * 2014-07-11 2016-01-26 H. Stuart Campbell Inhaler mouthpiece
US9700689B2 (en) 2002-05-21 2017-07-11 Trudell Medical International Medication delivery apparatus and system and methods for the use and assembly thereof
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US3998226A (en) * 1975-09-22 1976-12-21 Edward G. Gomez Inhalation device for encapsulated concentrates
DE2642174A1 (de) * 1975-09-29 1977-04-07 American Cyanamid Co Vorrichtung zum abgeben eines aerosols
FR2325391A1 (fr) * 1975-09-29 1977-04-22 American Cyanamid Co Distributeur d'aerosol
DK154049B (da) * 1975-09-29 1988-10-10 American Cyanamid Co Inhalator
US3994421A (en) * 1975-09-29 1976-11-30 American Cyanamid Company Unitary therapeutic aerosol dispenser
US4114615A (en) * 1975-12-12 1978-09-19 Aktiebolaget Draco Aerosol inhalation device
US5074294A (en) * 1988-06-22 1991-12-24 Chiesi Farmaceutici S.P.A. Device for dispensing metered amounts of aerosol for inhalation
US5040527A (en) * 1990-12-18 1991-08-20 Healthscan Products Inc. Metered dose inhalation unit with slide means
WO1992011048A1 (en) * 1990-12-18 1992-07-09 Healthscan Products, Inc. Metered dose inhalation unit
AU641074B2 (en) * 1990-12-18 1993-09-09 Healthscan Products, Inc. Metered dose inhalation unit
US5186164A (en) * 1991-03-15 1993-02-16 Puthalath Raghuprasad Mist inhaler
US6709650B1 (en) 1991-04-10 2004-03-23 Elam Drug Delivery Limited Spray-dried microparticles and their use as therapeutic vehicles
US5993805A (en) * 1991-04-10 1999-11-30 Quadrant Healthcare (Uk) Limited Spray-dried microparticles and their use as therapeutic vehicles
US5653962A (en) * 1991-12-12 1997-08-05 Glaxo Group Limited Aerosol formulations containing P134a and particulate medicaments
US20030143163A1 (en) * 1991-12-12 2003-07-31 Glaxo Group Limited Medicaments
US5674472A (en) * 1991-12-12 1997-10-07 Glaxo Group Limited Canisters containing aerosol formulations containing P134a and fluticasone propionate
US5676929A (en) * 1991-12-12 1997-10-14 Glaxo Group Limited Canister containing aerosol formulations containing P134a and particulate medicaments
US5683676A (en) * 1991-12-12 1997-11-04 Glaxo Group Limited Canister containing aerosol formulations containing P134a and particulate medicaments
US5736124A (en) * 1991-12-12 1998-04-07 Glaxo Group Limited Aerosol formulations containing P134a and particulate medicament
US5744123A (en) * 1991-12-12 1998-04-28 Glaxo Group Limited Aerosol formulations containing P134a and particulate medicaments
US5817293A (en) * 1991-12-12 1998-10-06 Glaxo Group Limited Canister containing aerosol formulations containing P134a and particulate medicaments
US6919069B2 (en) 1991-12-12 2005-07-19 Glaxo Group Limited Aerosol formulation containing particulate formoterol, propellant and polar cosolvent
US6893628B2 (en) 1991-12-12 2005-05-17 Glaxo Group Limited Aerosol formulations containing P134a and particulate medicament
US5922306A (en) * 1991-12-12 1999-07-13 Glaxo Group Limited Aerosol formulations containing P134a and particulate medicament
US5658549A (en) * 1991-12-12 1997-08-19 Glaxo Group Limited Aerosol formulations containing propellant 134a and fluticasone propionate
US20050207991A1 (en) * 1991-12-12 2005-09-22 Glaxo Group Limited Aerosol formulations containing P134a and particulate medicament
US20050089477A1 (en) * 1991-12-12 2005-04-28 Glaxo Group Limited Medicaments
US6200549B1 (en) 1991-12-12 2001-03-13 Glaxo Group Limited Aerosol formulation containing P134a and particulate medicament
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US6238647B1 (en) 1991-12-12 2001-05-29 Glaxo Group Limited Aerosol formulations containing salmeterol xinafoate, an anticholinergic agent and tetrafluoroethane
US6251368B1 (en) 1991-12-12 2001-06-26 Glaxo Group Limited Pharmaceutical aerosol formulation containing a particulate medicament, a propellant and substantially free of a surfactant
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US6306369B1 (en) 1991-12-12 2001-10-23 Glaxo Group Limited Aerosol formulations containing P134a and particulate medicament
US6333023B1 (en) 1991-12-12 2001-12-25 Glaxo Group Limited Aerosol formulation containing particulate formoterol, propellant and polar cosolvent
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US20050232873A1 (en) * 1991-12-12 2005-10-20 Glaxo Group Limited Aerosol formulation containing particulate formoterol, propellant and polar cosolvent
US20030198600A1 (en) * 1991-12-12 2003-10-23 Glaxo Group Limited Aerosol formulation containing particulate formoterol, propellant and polar cosolvent
US5674471A (en) * 1991-12-12 1997-10-07 Glaxo Group Limited Aerosol formulations containing P134a and salbutamol
US20030165437A1 (en) * 1991-12-12 2003-09-04 Glaxo Group Limited Aerosos formulations containing P134a and particulate medicament
US7101534B1 (en) 1991-12-18 2006-09-05 3M Innovative Properties Company Suspension aerosol formulations
US7105152B1 (en) 1991-12-18 2006-09-12 3M Innovative Properties Company Suspension aerosol formulations
US6743413B1 (en) 1991-12-18 2004-06-01 3M Company Suspension aerosol formulations
US20040197273A1 (en) * 1991-12-18 2004-10-07 3M Company Suspension aerosol formulations
US20030202944A1 (en) * 1993-10-26 2003-10-30 Vectura Limited Carrier particles for use in dry powder inhalers
US8137657B2 (en) * 1993-10-26 2012-03-20 Vectura Limited Carrier particles for use in dry powder inhalers
US5839429A (en) * 1994-03-25 1998-11-24 Astra Aktiebolag Method and apparatus in connection with an inhaler
US5916540A (en) * 1994-10-24 1999-06-29 Glaxo Group Limited Aerosol formulations containing P134A and/or P227 and particulate medicament
US5598836A (en) * 1995-05-26 1997-02-04 Healthscan Products, Inc. Metered dose inhalation unit with slide means
US5976573A (en) * 1996-07-03 1999-11-02 Rorer Pharmaceutical Products Inc. Aqueous-based pharmaceutical composition
BG64585B1 (bg) * 1996-07-03 2005-08-31 Rorer Pharmaceutical Products Inc Фармацевтичен състав на водна основа, метод за получаване и използването му
US20070031887A1 (en) * 1996-07-03 2007-02-08 Soo-Il Kim Aqueous-based pharmaceutical composition
US6143329A (en) * 1996-07-03 2000-11-07 Rorer Pharmaceutical Products Inc. Aqueous-based pharmaceutical composition
US7977045B2 (en) 1996-07-03 2011-07-12 Aventis Pharmaceuticals Inc. Aqueous-based pharmaceutical composition
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US6345617B1 (en) 1997-09-26 2002-02-12 1263152 Ontario Inc. Aerosol medication delivery apparatus and system
USRE43174E1 (en) 2000-04-11 2012-02-14 Trudell Medical International Aerosol delivery apparatus
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US7025058B2 (en) 2001-04-26 2006-04-11 New England Pharmaceuticals, Inc. Metered dose delivery device for liquid and powder agents
US20030015191A1 (en) * 2001-04-26 2003-01-23 New England Pharmaceuticals, Inc. Metered dose delivery device for liquid and powder agents
US8470301B2 (en) 2002-04-17 2013-06-25 Nektar Therapeutics Particulate materials
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US9616060B2 (en) 2002-04-17 2017-04-11 Nektar Therapeutics Particulate materials
US8080236B2 (en) 2002-04-17 2011-12-20 Nektar Therapeutics Uk, Ltd Particulate materials
US20030223939A1 (en) * 2002-04-17 2003-12-04 Andreas Kordikowski Particulate materials
US8973571B1 (en) 2002-05-02 2015-03-10 Pre Holding, Inc. Aerosol medication inhalation system
US7562656B2 (en) 2002-05-02 2009-07-21 Hydrate, Inc. Aerosol medication inhalation system
US20090090355A1 (en) * 2002-05-02 2009-04-09 Pari Innovative Manufacturers Aerosol medication inhalation system
US8074641B2 (en) 2002-05-02 2011-12-13 Pre Holdings, Inc. Aerosol medication inhalation system
US8459252B2 (en) 2002-05-02 2013-06-11 Pari Innovative Manufacturers, Inc. Aerosol medication inhalation system
US9308335B2 (en) 2002-05-02 2016-04-12 Pre Holding, Inc. Aerosol medication inhalation system
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US9814849B2 (en) 2002-05-21 2017-11-14 Trudell Medical International Medication delivery apparatus and system and methods for the use and assembly thereof
US20070253913A1 (en) * 2003-09-10 2007-11-01 Nahed Mohsen Aerosol formulations for delivery of dihydroergotamine to the systemic circulation via pulmonary inhalation
US9027551B2 (en) 2004-09-13 2015-05-12 Oriel Therapeutics, Inc. Dry powder inhalers that inhibit agglomeration, related devices and methods
US8365725B2 (en) * 2004-09-13 2013-02-05 Oriel Therapeutics, Inc. Dry powder inhalers that inhibit agglomeration, related devices and methods
US20080127971A1 (en) * 2004-09-13 2008-06-05 Michael King Dry Powder Inhalers that Inhibit Agglomeration, Related Devices and Methods
US8123761B2 (en) * 2004-10-15 2012-02-28 Meda Ab Device for removing a tick
US20100191252A1 (en) * 2004-10-15 2010-07-29 Laboratory Tickner B.V. Device for removing a tick
US20120109153A1 (en) * 2004-10-15 2012-05-03 Meda Ab Method for Removing a Tick
US8366722B2 (en) * 2004-10-15 2013-02-05 Meda Ab Method for removing a tick
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US20080287451A1 (en) * 2007-02-11 2008-11-20 Cook Robert O Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile
US20100081664A1 (en) * 2007-02-11 2010-04-01 Map Pharmaceuticals, Inc. Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile
US8119639B2 (en) 2007-02-11 2012-02-21 Map Pharmaceuticals, Inc. Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile
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US10172853B2 (en) 2007-02-11 2019-01-08 Map Pharmaceuticals, Inc. Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile
US20100284940A1 (en) * 2007-02-11 2010-11-11 Map Pharmaceuticals, Inc. Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile
US9833451B2 (en) 2007-02-11 2017-12-05 Map Pharmaceuticals, Inc. Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile
US20110171141A1 (en) * 2009-06-26 2011-07-14 Kellerman Donald J Administration of dihydroergotamine mesylate particles using a metered dose inhaler
USD797922S1 (en) 2013-02-14 2017-09-19 Clement Clarke International Limited Spacer for inhaler
USD778432S1 (en) 2013-02-14 2017-02-07 Clement Clarke International Limited Spacer for inhaler
USD744636S1 (en) * 2013-02-14 2015-12-01 Clement Clarke International Limited Spacer for inhaler
US10207065B2 (en) 2013-07-12 2019-02-19 John H. Silva Mouthpiece for inhalers
USD748242S1 (en) * 2014-07-11 2016-01-26 H. Stuart Campbell Inhaler mouthpiece

Also Published As

Publication number Publication date
GB1471917A (en) 1977-04-27
FR2234905A1 (de) 1975-01-24
PH11643A (en) 1978-05-08
IE40616B1 (en) 1979-07-18
FR2234905B1 (de) 1980-09-12
SU537614A3 (ru) 1976-11-30
DE2415360C2 (de) 1982-10-28
CH620207A5 (de) 1980-11-14
ZA741633B (en) 1975-03-26
NL7404626A (de) 1974-12-31
CH577832A5 (de) 1976-07-30
BE813512A (fr) 1974-10-09
AR198562A1 (es) 1974-06-28
CS182257B2 (en) 1978-04-28
CA1043208A (en) 1978-11-28
DK152967C (da) 1988-10-24
IL44401A0 (en) 1974-06-30
ATA299974A (de) 1977-07-15
NL178655B (nl) 1985-12-02
DK152967B (da) 1988-06-06
SE405448B (sv) 1978-12-11
JPS5049886A (de) 1975-05-02
SE7405022L (de) 1974-12-30
PL89980B1 (de) 1976-12-31
JPS6010737B2 (ja) 1985-03-19
DD125188A5 (de) 1977-04-06
ES427755A1 (es) 1976-08-01
IL44401A (en) 1976-10-31
IE40616L (en) 1974-12-27
DK343874A (de) 1975-02-17
DE2415360A1 (de) 1975-01-23
YU36435B (en) 1984-02-29
IT1003994B (it) 1976-06-10
NL178655C (nl) 1986-05-01
YU98974A (en) 1982-02-25
AT342211B (de) 1978-03-28
AU6676274A (en) 1975-09-18

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