Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
  • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
  • A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
  • A01N25/04—Dispersions, emulsions, suspoemulsions, suspension concentrates or gels
  • A01N25/06—Aerosols
• • C—CHEMISTRY; METALLURGY
  • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
  • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
  • C09K3/00—Materials not provided for elsewhere
  • C09K3/30—Materials not provided for elsewhere for aerosols
• • C—CHEMISTRY; METALLURGY
  • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
  • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
  • C11D17/00—Detergent materials or soaps characterised by their shape or physical properties
  • C11D17/0043—For use with aerosol devices

Definitions

• This invention relates to self-propelling. power-dispensing compositions capable of dispensing powdered material in aerosol form and to a means for dispensing a dry powder in aerosol form having controlled particle size.
• compositions of the invention comprise a finely-divided active solid material or powder suspended in a liquified propellant, in which the solid material is substantially insoluble, and a non-ionic surface-active agent which is liquid at room temperature (65 F.), or ambient temperatures.
• he finely divided powder may constitute from about 0.01 to 20% by weight of the total composition. Desirably it shall constitute from about 0.05% to 10%, and referably 0.1 to 3%, by weight of the total composition.
• the surface-active agent may constitute from about 0.1 to 20%, desirably between about 0.25 and 5%, and preferably, for medicinal purposes, between about 0.25 and 1%, by weight of the total composition, with the liquified propellant constituting the remainder of the composition.
• the concentration of surfaceactive'agent is kept at a minimum as it may tend to solubilize the powder in the propellant, which is undesirable for reasons which will be explained below.
• the particle-size of the powder should desirablybe uniform and not greater than microns diameter, since larger particles may tend to agglomerate, separate from the suspension and may clog thevalve or orifice. of the container.
• the particle size should be less than 25- microns in diameter.
• the. particlesize of the finely-divided solid powder should for physiological reasons be less than 25 microns and preferably less than 10 microns in diameter.
• the size of the particles of powder should be substantially uniform. There is no lower limit of particle size except'that'which is imposed by the use to which the aerosol produced is to be put. Where the powder is a solid medicament, the lower limit of particle size is that which will be readily absorbed and retained on or in body tissues. When particles less than one micron in diameter are administered by inhalation they tend to be re-exhaled by the patient.
• the finely-divided powder should be substantially insoluble in each of the liquified propellant, the surface-active agent and in a liquified propellant-surface-active mixture.
• the powder is substantially soluble, crystal growth may occur and the particle size of the aerosolized powder when dispensed cannot be controlled.
• compositions of the invention are intended to be used for dispensing powders in aerosol form by operating the valve of a pressuretight container charged with the compositions, it is desirable that the particle size of the suspended powder be regulated and agglomeration reduced. It is clear that if agglomeration of the powder takes place, it may tend to clog the narrow valve orifice and render the dispensing device inoperative, or it a metering valve is employed, it may be rendered inaccurate. This may lead to inaccurate dosages, which in the case of highly potent medicinals may lead to undesirable results. In addition to increasing 3 make the suspension unstable and of unsuitable appearance. In the case of powdered medicinals, adsorption in the body may be made ineffective. Consequently, it is desirable that the finely-divided powder be substantially insoluble in the other components of the compositions.
• a finely-divided powder such as a medicament
• a finely-divided powder tends to be somewhat soluble in the mixture of surfaceactive agent and liquified propellant
• a less soluble form of the powder For example, instead of employing the base phenylephrine, its hydrochloride may .be employed.
• different liquified propellants may be employed in which the powder is less solubie.
• compositions of the invention Illustrative of the versatility of the compositions of the invention is the fact that the solid components may be amorphous or crystalline in nature. We prefer to use crystalline materials, as is indicated by the specific examples given below. Early efforts to produce self-propelling powder dispensing compositions showed that even to obtain compositions having only borderline properties, it was necessary to limit the solid materials employed to amorphous materials.
• compositions of the present invention do not require the presence of a polar solvent, such as water.
• a polar solvent such as water.
• the compositions may be substantially anhydrous.
• moisture control is important at all stages of processing.
• Another means of controllingand reducing the moisture content of the composition is to introduce before closing the container in which the composition is packaged, small fragments of an anhydrous, nonreactive desiccant, such as silica gel or calcium sulfate. This reduces the moisture content of the liquid phase of the composition below that which causes agglomeration.
• an anhydrous, nonreactive desiccant such as silica gel or calcium sulfate. This reduces the moisture content of the liquid phase of the composition below that which causes agglomeration.
• desiccant is sutficien-t for a 10 ml. container charged with composition.
• the solid active component to be aerosolized may be a: medicament, such as a vasoconstrictive amine or its acid-addition salts, a hormone, enzyme, alkaloid, steroid, analgesic, bronchodilator, antihistamine, antitussive, an-
• medicament such as a vasoconstrictive amine or its acid-addition salts, a hormone, enzyme, alkaloid, steroid, analgesic, bronchodilator, antihistamine, antitussive, an-
• medicaments which may be employed are: isoproterenol [alpha- (isopropylaminomethyl)protocatechuyl alcohol] hydro- .chloride or sulfate, phenylephrine, phenylpropanolamine,
• glucagon adrnochrome, trypsin, epinephrine, ephedrine, narcotine, codeine, atropine, morphine, dihydromorphinone, ergotamine, scopolamine, methapyrilene, cyanocobalamin, and colchicine.
• Others are antibiotics such as ncomycin, streptomycin, penicillin, procaine penicillin, tetracycline, chlorotetracycline and hydroxytetracycline;
• the active solid component may also be a cosmetic substance such as talc, an antiperspirant such as aluminum chlorohydrate,
• a lubricant such as graphite and other finely-divided materials; as well as other usefulsubstances.
• the liquified propellant employed is one which is a gas at room temperature (65 F.) and atmospheric pressure (760 mm. of mercury), i.e., it shall have a boiling point below 65 F. at atmospheric pressure.
• the liquified propellant should be non-toxic.
• suitable liquitied propellants which may be employed are the lower alkanes containing up to five carbon atoms, such as butane and pentane, or a lower alkyl chloride, such as methyl, ethyl or propyl chlorides.
• the most suitable liquified propellants are the fiuorinated aand fiuorochlorinated lower alkanes such as are sold under the trademark Freon. Mixtures of the above mentioned propellants may suitably be employed.
• the fiuorinated or flLlOIOChiOI'b nated lower alkane shall contain not more than two carhon atoms and at least one fluorine atom.
• Examples of these propellants are dichlorodifluoromethane (Freon l2), dichlorotetrafiuoroethane (Freon 1 l4) CClF .CC1F trichloromonofiuoromethane (Freon 11), dichloromonofluoromethane (Freon 2l) monochloroditluoromethane (Freon 22), trichlorotrifluoroethane (Freon 113), and monochlorotrifluorm methane (Freon l3).
• Propellants with improved vapor pressure characteristics may be obtained by using certain mixures of these compounds, e.g., Freon 11" with Freon 12, or Freon 12" with Freon 114.”
• the vapor pressure of the propellant employed shall itself be Between about 25 and 65 pounds per square inch gauge at 70 F., arid prefer bly between about 30 and 40 pounds per square inch gauge at that temperature.
• a one-component propellant defined for use in the composition was found to give a composition with gauge pressures in the range of 55 to 65 pounds per square inch at 70 R, which are usable safely with metal containers.
• the two-component propellants such as equal weight mixtures of "Freon 12 and Freon 11, were found to give gauge pressures in the range of 20 to 40 pounds per square inch at 70 R, which are usable safely with specially reinforced glass containers.
• valves of simple construction may be used, and there is no need to provide special nozzles and expansion chambers, as is usually required when dispensing materials surface coating, which may even be a mono-molecular film or layer, on the finely-divided powder which prevents the particles from agglomerating either while dispersed in the propellant or when in the valve of the container.
• the liquid, non-ionic, surface-active agent employed should have an hydrophile-lipophile balance (HLB) ratio of less than 10.
• HLB ratio is an empirical number which provides a guide to the surface-active properties of a surface-active agent. The lower the HLB ratio, the more lipophilic is the agent, and conversely, the higher the HLB ratio, the more hydrophiiic is the agent.
• the HLB ratio is well known and understood by the colloid chemist and its method of determination is described by W. C. Grifiin in the Journal of the Society of Cosmetic Chemists, vol. 1, No. 5, pages 311-326 (1949).
• the surface-active agent employed should have an HLB ratio of about 1 to 5. It is possible to employ surface-active agents which themselves do not possess an HLB ratio within these ranges, providing they are used in conjunction with other surface-active agents which have an HLB ratio which will provide a mixture having an HLB ratio within the prescribed range.
• Lubricants for the valve such as calcium stearate, which is without surfactant properties, were not found to be satisfactory, because they do not help to keep the powdered medicament uniformly dispersed in the pro pellant.
• the surfaceactive agent should be non-irritating and non-toxic.
• liquid non-ionic surfaceactive agents which may be employed in our compositions are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octoic, lauric, palmitic, stearic, linoleic, linolenic, eleostearic and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride such as, for example, ethylene glycol, glycerol, erythritol, arabitol, mannitol, sorbitol, the hexitol anhydrides derived from sorbitol (the sorbitan esters sold under the trademark Spans”) and the polyoxyethylene and polyoxypropylene derivatives of these esters.
• an aliphatic polyhydric alcohol or its cyclic anhydride such as, for example, ethylene glycol, glycerol, erythritol, arabitol, manni
• sorbitan e.g., those sold under the trademarks Arlacel C (Sorbitan sesquioleate), Span 80 (sorbitan monooleate) and Span 85 (sorbitan trioleate).
• MYRJ 45 Polyoxyethylene Very good suspension, elumpy, stearate. sticks to container, breaks very rapidly, lubrieates valve.
• Bi-i Polyoxyctliylenelauryl Very poor suspension, clumpy,
• compositions of the invention employing certain finely-divided powders there is a tendency to form a layer of powder at the surface of the propellant in the container and that these layers tend to deposit or cake" powdered material on the container walls above the liquid level. This has been found to occur only with those powders which have a specific gravity less than that of the propellant.
• the undesirable deposition or caking which results where the specific gravity of the finely divided powder is substantially less than that of the propellant can be overcome by lowering the specific gravity of the liquid phase, for example by using a propellant of lower specific gravity, such as butane, or by increasing the specific gravity of the solid active powder component, for example in the case of phenylephrine by using the bitartrate salt instead of hydrochloride.
• a propellant of lower specific gravity such as butane
• the specific gravity of the solid active powder component for example in the case of phenylephrine by using the bitartrate salt instead of hydrochloride.
• auxiliary solid may be of any chemical type, provided that it is compatible with the other ingredients and insoluble in the propellant.
• an inorganic compound such as sodium sulfate, calcium chloride or sodium chloride.
• an organic material such as powdered lactose, sucrose, epinephrine bitartrate, neomycin sulfate, or graphite.
• the auxiliary solid when used in medicinal and cosmetic preparations, should be non-toxic and nonirritant. In all cases it should be without deleterious effect on the properties of the dispensed product or on the user.
• the particle size of the auxiliary solid should pp in this suitable for inhalation therapy.
• PU is equal to or greater than pp (3) thus when q equals 11, equals zero. less than [312, the following exists:
• compositions of the invention may-be used to apply measured amounts of aerosolized solid medicaments into body cavities such as the throat or nose. They also provide a means of producing aerosolized medicaments Inhalation therapy is prompt through the intimate contact with the blood through the alveolar membrance. It also enablm drugs to act directly on respiratory sites without engendering undesirable systemic effects as happens often When drugs are administered by other routes. With very volatile substances inhalation approaches intravenous therapy in rapidity of. action. It willoften avoid the necessity of parenteral injections.- Previously aerosols for this purpose have been prepared by nebulizing aqueous solutions,
• a container equipped with a valve is filled with a propellant containing the finely-divided powder in suspension.
• a container may first be charged with a weighed amount of dry powder which has been ground to a predetermined particle size, or in a slurry of powder in the cooled liquid propellant.
• the powder and the surface-active agent may be triturated or homogenized first into a uniform paste, for instance, by a pestle and mortar. This paste is then dispersed in the cooled liquefied propellant. This procedure fosters uniform wetting of the powder particles.
• a container may also be filled by introducing powder and propellant by the normal cold filling method, or a slurry of the powder in that component of the propellant which boils above room temperature may be placed in the container, the valve sealed in place, and the balance of the propellant may be introduced by pressure filling through the valve nozzle.
• the powder On operating the valve, the powder will be dispensed in a stream of propellant, which will vaporize providing an aerosol of dry powder.
• the preparation of the product care is desirably exercised to minimize the absorption of moisture where the powder is water-soluble. This may be accomplished by operat-' .ing in a dehumidified atmosphere using only dry materials and equipment.
• Example 1 Percent Hydrocortisone acetate, crystalline (more than 90% by weight within the particle size range of l to 5 microns) 3.0 Span 85 (sorbitan trioleate) 1.0 Freon l1 (trichloromonofluoromethane) 30.0 Freon 114 (dichlorotetrafiuoroethane) 41.0 Freon 12 (dichlorodifiuoromethane) 25.0
• Example 2 Gm. Trypsin, amorphous (more than 90% by weight within the particle size range of l to 10microns) 0.10
• Example 3 Percent Pre dnisolone acetate, crystalline (more than 90% by weight within the particle size range of l to 5 microns) 0.5 Span 85 (sorbitan trioleate) 0.5 Propellant B 99.0
• Prcpellant B consists of:
• Freon 11 (trichloromoncfiuoromethane) 10.0 Freon 114 (dichlorotetrafluorcethane) 50.4 Freon 12" (dichlorctetrafluoroethanc) 31.6 Butane a; 8.0
• Example 4 ACTH (adrenocorticotropin) (amorphous) (l USP units/mg.) (more than 90% by weight within the particle size range, of 1 to 20 micron's) N 1.00
• Insulin amorphous (more than 90% by weight I within the particle size range of 1 to 5 microns) 0.25 Span 85 (sorbitan trioleate) 0.25 Freon W (as defined in Example 2) 99.50
• Example 7 Epinephrine, crystalline (free base) (more than 90% by weight within the particle size range of 1 to 5 microns 0.28 Span 85 (sorbitan. trioleate) 0.25 Freon 11 (trichlorornonofluorometha-ne) 5.00
• Example 8 Epinephrine bitartrate, crystalline (more than 90% by weight withinthe particle size range of 1 to 5 microns) 0.50 Span 85(sorbitan trioleate) 0.50 Freon 11"'(trichloromonofluoromethane) 49.50 Freon '12 (dichlorodifluoromethane) .l- 49.50
• Example 9 Isopropylarterenol hydrochloride, crystalline (more than 90% by weight within the particle size range of l to 5 microns) 0.25 Span (sorbitan trioleate) 0.25 Freonll (trichlorornonofluoromethane) 49.75 Freon l2 (dichlorodifiuorcmethane) 49.75
• Example 10 Phenylephrine hydrochloride, crystal-line (more than by weight within the particle size range of l to 25 microns) 0.25 Ncomycin sulfate 0.11 Hydrowrtisone 0.04 Span S5" (sorbitan trioleate) 0.25 Freon ll (trichloromonofiuoromethane) 49.675 Freon l2 (dichlorodifluorornethane) 49.675
• Example 12 Hydrocortisene acetate, crystalline (more than 90% by weight within the particle size range 'of l to 5 microns) 0.50
• Surfactant 6-1087 polyoxyethylene sorbitol hexaoleate
• a, 0.50 Propcllant C 99.00
• Example 13 Percent Hydrocortisone acetate, crystalline (more than 90% by weight within the particle size range of 1 to 5 microns) 0.50 Arlacel C (sorbitan sesquioleate) 0.50 Propellant C (as defined by Example 12) 99.00
• Example 14 Hydrocortisone acetate, crystalline (more than 90% by weight within the particle size range of 1 to 5 microns) 0.50 Span 80 (sorbitan monoleate) 0.50 Propellan-t- C (as defined-by Example 12) 99.00
• Example 15 Hydrocortisone acetate, crystalline (more than 90% by weight within the particle size range of 1 to 5 microns) 0.50 Span S5 (sorbitan trioleate) 0.50 Propellant C-(as defined by Example 12) 99.00
• Narcotine crystalline (more than 90% by weight within the particle size range of 1 to microns) 10.00 Span 85 (sorbitan trioleate) 1.00 Freon W (as defined by Example 2) 89.00
• Example 17 "Dilaudid, crystalline (dihydrornorphinone hydrochloride) (more than 90% by weight within the particle size range of 1 to 5 microns) 0.5 Span 85 (sorbitan trioleate) 1.0 Freon 11 (trichloromonofiuoromethane) 30.0 Freon W" (as defined by Example 2) 68.5
• This composition is useful for polishing optical components.
• Example 19 Percent Hydrocortisone acetate, crystalline (more than 90% 'by weight within the particle size range of 1 to 5 microns) 0.5 Olive oil 0.5 Freon 11 30.0 Freon W (as defined by Example 2) 69.0
• Example 20 Phenylephrine hydrochloride (crystalline), micronized 0.25 Phenylpropanolamine hydrochloride (crystalline), micronized 0.50 'Neomycin sulfate (crystalline), micronized 0.10 Hydrocortisone (crystalline), micronized 0.04 Sodium sulfate (anhydrous), micronizcd 0.35 Span 85" (sorbitan trioleate) 0.80 Prd'pellant S 97.96
• Propellant S consists of:
• Example 25 Phcnylephrine hydrochloride (crystalline), micronized 1.0 Neomycin sulfate (crystalline), micronized 3.0 Span 85 (sorbitan trioleate) 1.0 Propellant S (as defined by Example 20) 95.0
• Propellant S-2 consists of:
• Neomycin sulfate (crystalline), micronized 0.08
• Propellant X consists of:
• Freon 12 (dichlorodifluoromethane) 30 Freon 11 (trichloromonofiuoromethane) 30 Freon 114 (dichlorotetrafluoroethane) 40
• Phenylephn'ne hydrochloride (c ystalline), mi-
• Neomycin sulfate crystalline
• micronized 0.08 Thenylpy'ramine hydrochloride crystalline
• Example 31 Isoproterenol sulfate, crystalline, micronized 0.15 Span 85 (sorbitan trioleate) 0.50 Freon 113 (trichlorotrifiuoroethane) 0.95 Freon 11 (trichloromonofiuoromethane) 24.60 Freon 114 (dichlorotetrafluoroethane) 24.60 Freon 12 (dichlorodifiuoromethane) 49.20
• Example 34 Crystalline glucagon, micronized 0.156 "Span 85- 0.468 Propellant S" (as defined by Example 20) 99.376
• Example 35 Anhydrous cyanocobalamin, crystalline, micronized 0.039 Span 85 0.25 Propellant S (as defined by Example 20) 99.711
• Example 36 Chlorotetracycline hydrochloride, crystalline, mi-
• Example 37 Adrenochrome, crystalline, micronized 1.785 Span 85 Propellant S" (as defined by Example 20) 97.215
• a self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form comprising between about 0.01% and 20% by weight of a finely-divided powder of a particle size less than about microns suspended in a liquefied propellant having a vapor pressure of at least about 13 lbs.
• said composition shall contain not more than about 300 parts per million of moisture.
• a self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder comprises isoproterenol hydrochloride.
• a self-propelling, powder dispensing pharmaceutical composition capable of providing a medicament in aerosol form suitable for inhalation therapy, comprising a liquefied non-toxic propellant having a vapor pressure of at least about 13 lbs. per square inch gauge at 70 F., between about 0.01% and 20% by weight of a finelydivided therapeutically active powdered medicament of substantially uniform particle size of less than about 100 microns suspended in said propellant, and between about 0.1% and 20% by weight of a liquid non-toxic non-ionic surface active agent having a hydrophile-lipophile balance ratio of less than about 10 and being soluble in said liquefied propellant; said finely-divided powder being substantially insoluble in the mixture of propellant and surface active agent; and when said finely-divided powder is watersoluble, said composition shall contain not more than about 300 parts per million of moisture.
• a self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form comprising a composition as defined in claim 1, wherein the specific gravity of the finely divided powder is at least as great as that of the liquefied propellant.
• a self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form comprising a composition as defined by claim 1 having "11 units by weight of a useful substance of specific gravity as a finely-divided powder and aunits by weight of an auxiliary solid substance of specific gravity p in powdered form suspended in a liquid of specific gravity pp wherein the minimum value of is expressed as follows:
• a self-propelling powder dispensing composition capable of producing a useful substance in aerosol form according to claim 22', wherein the auxiliary solid is sodium sulfate.
• a self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form according to claim 22, wherein the auxiliary solid is calcium chloride.
• a self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form according to claim 22, wherein the auxiliary solid is lactose.
• a self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form according to claim 22, wherein the auxiliary solid is sucrose.
• a package comprising a pressure-tight container having a valve-controlled opening and containing alpharmaceutical composition capable of providing a measured dose of medicament in aerosol form suitable for inhalation therapy, comprising a composition as defined by claim 20 31.
• pages 324, 328 read pages 324 through 328 Signed and sealed this 24th day of April 1962.
• pages 324, 328 read pages 324 through 328 Signed and sealed this 24th day of April 1962.

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• 1957
  • 1957-04-30 BE BE556587D patent/BE556587A/xx unknown
• 1958
  • 1958-01-03 US US706908A patent/US3014844A/en not_active Expired - Lifetime
  • 1958-01-27 DE DER22567A patent/DE1178975B/de active Pending
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  • 1958-01-29 FR FR756970A patent/FR1228811A/fr not_active Expired
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  • 1958-01-31 NL NL224547A patent/NL106832C/xx active

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