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
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
  • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
  • B65D83/00—Containers or packages with special means for dispensing contents
  • B65D83/14—Containers for dispensing liquid or semi-liquid contents by internal gaseous pressure, i.e. aerosol containers comprising propellant
  • B65D83/141—Containers for dispensing liquid or semi-liquid contents by internal gaseous pressure, i.e. aerosol containers comprising propellant specially adapted for specific contents or propellants

Definitions

• Aerosol formulations comprising a finely divided solid medicament, a propellant, and an anionic surface-active agent selected from the group consisting of alkali metal, ammonium and amine salts of dialkyl sulphosuccinic acids wherein the alkyl groups contain from 4 to 12 carbon atoms, and alkali metal, ammonium and amine salts of alkylbenzene sulphonic acids wherein the alkyl groups contain from 8 to 14 carbon acids.
• the present invention relates to powdered medicament formulations for use in pressurized dispensing containers (hereinafter termed aerosol formulations and containers).
• Aerosol formulations find wide use inter alia, as a means of applying a medicament to a patient, for ex ample by way of inhalation.
• such formulations comprise the material to be dispensed in admixture with a propellant therefor, which propellant is usually a liquefied material which is gaseous at ambient t mperatures.
• propellant is usually a liquefied material which is gaseous at ambient t mperatures.
• Such formulations are held in a container provided with a valved outlet, which may or may not be adapted to release uniform doses of material, the volatilisation of the liquefied material generating a pressure within the container.
• the valved outlet Upon operation of the valved outlet, the contents of the container are discharged as a fine spray.
• the general construction of the container and valved outlet are well known in the aerosol art, as is the use of a wide variety of liquefied materials, notably halogenated hydrocarbons, as propellants.
• the material to be dispensed is not soluble in the propellant material to be used, as may be the case with a finely divided solid medicament, it is necessary to have present in the aerosol formulation a suspending agent to ensure that the solid material is satisfactorily suspended.
• a suspending agent to ensure that the solid material is satisfactorily suspended.
• surface-active agents which were non-ionic in nature to achieve satisfactory suspension of the solid medicament and other materials, since ionic surface-active agents were considered to have too low a solubility in the liquefied propellant medium to be effective.
• the non-ionic surfaceactive agents which are in current commercial use include the ethylene oxide condensates of phenols and esters or partial esters of fatty acids. Typical of such compounds are those materials sold under the trademarks Span and Arlacel.
• it has also been considered necessary to use comparatively large amounts of these materials to achieve satisfactory results and the use of 100% or more by weight of surface-active agent based on the weight of solid material to be suspended is commonplace in commercial formulations
• compositions especially one which is to be ingested, e.g. inhaled, by the user, it is highly desirable that the composition Patented Feb. 2, 1971 contain the minimum of materials, other than those which are clearly inactive diluents, which could in any way affect the user detrimentally.
• reduction in the amounts of non-ionic surface-active agents in formulations of the type described above has resulted in formulations in which the solid materials were not satisfactorily suspended.
• anionic surfaceactive agents may be used as suspending agents in powder aerosol formulations, and that these anionic surface-active agents may be used at far lower concentration than has been hitherto considered necessary for the non-ionic surface-active agents in present use.
• anionic surface-active agents of the invention has the advantages that the amount of material in the formulation other than the pharmaceutical may be reduced to a level below that hitherto attained; that certain desirable propellants of low toxicity which are incompatible with non-ionic surface-active agents may be used; and that a material, which is water-soluble and hence does not inhibit the assimilation of the powdered medicament upon presentation to the mucous membranes, is used whereas non-ionic surface-active agents are generally water-insoluble and cover the powder particles as a comparatively thick waterinsoluble coating.
• a further surprising feature of the use of the anionic surface-active agents of the invention is that in many cases the amount of surface-active agent required to suspend the solid material does not depend directly on the amount of solid material present.
• anionic surface-active agents of the invention should be effective at all in powder aerosol formulations is wholly unexpected since other commonly used anionic surface-active agents have been found to be totally ineffective, in that they were not sufficiently soluble in the propellant medium to provide solutions of equivalent concentration to those used with non-ionic surface-active agents and at the very low concentration of compound in liquefied propellant medium, which could be achieved before the compounds themselves came out of solution, they were not effective as suspension acids.
• the present invention provides a composition which comprises (a) a finely divided solid medicament having a particle size of less than microns, (-b) a propellant and (c) an anionic surface-active agent selected from the group consisting of (i) alkali metal, ammonium and amine salts of dialkyl sulphosuccic acids wherein the alkyl groups contain from 4 to 12 carbon atoms, and (ii) alkali metal, ammonium and amine salts of alkylbenzene sulphonic acids wherein the alkyl groups contain from 8 to 14 carbon acids; said medicament comprising from 0.025 to 20% by weight of the composition and said anionic surface-active agent comprising from about 0.01% to about 10% by weight of the solids content of the composition.
• an anionic surface-active agent selected from the group consisting of (i) alkali metal, ammonium and amine salts of dialkyl sulphosuccic acids wherein the alkyl groups contain from 4 to 12 carbon atoms, and (
• the surface-active agents for present use are preferably selected from the group comprising the salts of dialkyl sulphosuccinic acids wherein the alkyl groups are the same and contain from 4 to 9 carbon atoms, notably the salts of dibutyl-, dioctyland dinonylsulphosuccinic acids; and the salts of alkylbenzene sulphonic acids wherein the alkyl groups contain from 10 to 12 carbon atoms,
• the salts for present use may be the alkali metal, ammonium or amine salts of the acids. It will be appreciated that the salts should be selected from amongst those which are therapeutically acceptable. It is preferred to use the sodium salts of the acids.
• the medicament is a finely divided solid, having a particle size of less than 100 microns, and preferably is of a particle size of 1-25 microns.
• medicaments which may be used include isoprenaline sulphate, atropine methonitrate, adrenaline acid tartrate, ephedrine hydrochloride, ergotamine tartrate, diphenhydramine hydrochloride, hydrocortisone acetate; antibiotics, for example penicillins, streptomycin and tetracycline; and mixtures of any of these together or with other medicaments.
• the medicament suitably comprises 0.025-20% by weight of the total composition, although larger or smaller proportions may be used if desired. According to a preferred embodiment the total composition contains 0.1-2% by weight of medicament.
• the anionic surface-active agent may, as indicated above, be used in very small amounts.
• the amount of the surface-active agent required is broadly related to the solids content of the suspension and to the particle size of the solids. In general it is only necessary to use 0.0l-2% of the anionic surface-active agent by weight of the solids content of the suspension. It is not necessary to use larger amounts than this and I have found that the use of amounts in excess of from 5% to of the solids content of the suspension provides no advantage.
• 0.05 to 0.2% of the anionic surface-active agent by weight of the total solids in the composition is obtained using 0.05 to 0.2% of the anionic surface-active agent by weight of the total solids in the composition.
• the propellant may be any of the conventional propellants used in aerosol formulations, for example halogenated hydrocarbons of the fluorohydrocarbon or fluorohalohydrocarbon type such as trichloromonofiuoromethane, dichlrodifiuoromethane, dichlorotetrafluoroethane, monochlorotrifiuoromethane, monochlorodifluoromethane and mixtures of any of these together or with other propellants.
• suitable propellants are those disclosed in, for example, US. Pat. 2,868,691 and sold under the trademark Freon.
• formulations are to be ingested it is preferred to use as liquefied propellants either difluorodichloromethane or dichlorotetrafluoroethane, or mixtures thereof.
• composition of the invention should desirably be substantially anhydrous, that is that the minimum feasible amount of water should be present.
• polar solvents for this purpose include ethyl alcohol and isopropyl alcohol.
• auxiliary solids may also be desired to add auxiliary solids to the formulation.
• the medicament is of density considerably less than that of the propellants, it may be suitable to add a solid inert diluent of high density of the same particle size, so that the density of the combined solids is similar to that of the propellants.
• Suitable inert solids for this purpose include sodium chloride and sodium sulphate.
• EXAMPLE 1 The following composition was prepared and incorporated in a pressurised aerosol package.
• This composition is useful for the relief of asthmatic conditions and used as an inhalant gives a dry spray which is readily absorbed by the mucous membranes.
• the composition was a stable suspension whose settling time was considerably longer than when no surfaceactive agent was present.
• EXAMPLE 3 Percent Ephedrine hydrochloride (particle size below 20 microns) 1.0 Sodium chloride (particle size below 20 microns) 1.0 Naphazoline nitrate (particle size below 20 micons) 0.1 Cineole 0.2 Sodium dioctylsulphosuccinate 0.015 Dichlorodifluoromethane 30.0
• Dichlorotetrafluoroethane to 100% This formulation is useful as a nasal decongestant.
• the composition was a stable suspension Whose settling time was considerably longer than when no surface-active agent was present.
• Ephedrine hydrochloride (of particle size less than 11 microns, 1%) was suspended in a solution of the surfaceactive agent (varying amounts) in monofluorotrichlord methane (to 100%) and the mixture subjected to high speed stirring in a Guisti stirrer for 5 minutes.
• suspensions were also prepared in the same manner using a typical non-ionic surface-active agent in current use in powder aerosol formulations, Arlacel 85 which is sorbitan trioleate. The suspensions were examined for:
• the anionic surface-active agent was an effective suspension aid over a wide range of low concentrations; that it was more effective than the non-ionic material even when used at 5% of the concentration of the nonionic; and that it was not until the concentration of the non-ionic surfaceactive agent was raised to 50.0% that it showed an im provement in effe'ctivity when compared to a concentration of 0.075% of anionic material, i.e. the non-ionic material was present in some 800 times as great an amount.
• a substantially anhydrous composition consisting essentially of (a) a finely divided solid medicament having a particle size less than microns, (b) a halogenated hydrocarbon propellant having no more than 2 carbon atoms and (c) an anionic surface-active agent se lected from the group consisting of sodium dioctylsulphosuccinate and sodium dodecylbenzene sulphonate; said medicament being present in from 0.025 to 20% by weight of the composition and said anionic surface-active agent being present in from about 0.05% to about 2% by weight of the solids content of the composition.
• composition as claimed in claim 1 wherein the anionic surface-active agent is sodium dioctylsulphosuccin-ate.
• composition as claimed in claim 1 whereln the 5 3,282,781 11/1966 Macek anionic surface-active agent is sodium dodecylbenzene sulphonate OTHER REFERENCES
• the composition as claimedfin claim 1 further 9 Di Giacomo: Drug and Cosmetic Industry, September taining an inert high denslty so11d of the same particle 1958; 79 3, me as the medlcament' 10 Schwartz et al.: Surface Active Agents and Detergents,

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Dispersion Chemistry (AREA)
• Mechanical Engineering (AREA)
• Emergency Medicine (AREA)
• Otolaryngology (AREA)
• Pulmonology (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicinal Preparation (AREA)

Applications Claiming Priority (1)

Publications (1)

Family

ID=10436603

Family Applications (1)

Country Status (6)

Cited By (33)

Families Citing this family (4)

• 1962
  • 1962-11-30 GB GB45282/62A patent/GB1063512A/en not_active Expired
• 1963
  • 1963-11-19 DE DEB74324A patent/DE1208036B/de active Pending
  • 1963-11-29 FR FR955430A patent/FR3384M/fr not_active Expired
• 1964
  • 1964-10-20 BE BE654599A patent/BE654599A/xx unknown
  • 1964-10-26 NL NL646412459A patent/NL144832B/xx unknown
• 1968
  • 1968-07-05 US US742521A patent/US3560607A/en not_active Expired - Lifetime

Also Published As

Similar Documents