US3282791A - Inhalation aerosol suspension of anhydrous disodium dexamethasone phosphate, propellents, and sorbitan trioleate - Google Patents

Inhalation aerosol suspension of anhydrous disodium dexamethasone phosphate, propellents, and sorbitan trioleate Download PDF

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Publication number
US3282791A
US3282791A US480509A US48050965A US3282791A US 3282791 A US3282791 A US 3282791A US 480509 A US480509 A US 480509A US 48050965 A US48050965 A US 48050965A US 3282791 A US3282791 A US 3282791A
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dexamethasone phosphate
sorbitan trioleate
propellents
inhalation aerosol
anhydrous disodium
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US480509A
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Thomas J Macek
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Merck and Co Inc
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Merck and Co Inc
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    • 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]

Definitions

  • This invention relates to pharmaceutical compositions, and more particularly, to self-propelling, organolepticallyacceptable aerosol compositions containing the water-soluble anti-inflammatory steroid, dexamethasone phosphate.
  • the present invention provides a self-propelling com- 7 position of the water soluble steroid dexamethasone phosphate in a dosage of dexamethasone phosphate substantially reduced compared to the usual oral or parenteral dose and in a composition which has an agreeable and acceptable taste.
  • the particle size of the dexamethasone phosphate should be between about 1 micron and about 10 microns, and preferably in the range of about 1 to 5 microns. It should constitute from 0.001 to 0.18% of the total composition by weight.
  • compositions of this invention include substantially anhydrous suspensions or dispersions of the solid dexamethasone phosphate disodium salt medicament uniformly dispersed or suspended throughout the nontoxic liquid propellant with the aid of a suitable dispersing agent.
  • This dispersing agent is sorbitan trioleate (sold as Span 85) and it is employed in the range of 0.01 to 2.0% by weight of the total composition.
  • the liquified propellant employed in the novel composition of this invention should be non-toxic and have a vapor pressure between about 15 and 70 pounds and preferably between about 20 and 30 pounds per square inch gauge at 70 F.
  • the propellants having the above characteristics are the fiuorinated'or fiuorochlorinated lower saturated aliphatic hydrocarbons.
  • the preferred propellants of this type are the halogenated alkanes containing not more than two carbon atoms and at least one fluorine atom.
  • trichl-oromonofiuoromethane trichl-oromonofiuoromethane, dichloromonofluoromethane, monochlorotrifiuoromethane, dichlorodifluoromethane, monochlorotrifluoromethane, dichloromonofluoromethane, and 1,2- dichloro-1,1,2,2-tetrafluoroethane.
  • These compounds are available commercially from E. I. du Pont de Nemours and Company under the trade name Freon, and from others under different trade names.
  • fluorinated or fiuorochlorinated lower saturated aliphatic hydrocarbons having the above-mentioned characteristics may be employed singularly or in compatible admixtures.
  • other non-toxic propellants having a vapor pressure without the limits prescribed above may be utilized in compatible admixtures with or without one or more propellants having the required vapor pressure providing that the vapor pressure of such mixtures is within the prescribed range.
  • This liquefied propellant constitutes substantially the entire remainder of the composition, although other ingredients amounting to as much as 1 to 2% of the total composition by'weight may be present.
  • the dexamethasone phosphate as the disodium salt is first ground, milled or micronized to a particle size in the range specified hereinabove. It is then dried by conventional methods to substantially remove any moisture which .may be present. A desired amount of finely divided and substantially anhydrous medicament is then suspended by means of dispersion agitation in a measured amount of the propellant or propellant mixture with the sorbitan trioleate, previously cooled to a temperature of about -25 F. The suspension is made by appropriate dilution, then without permitting the temperature of the suspension to rise above the boiling point of the propellant, the suspension is filled into a suitable container which may be metal,
  • the quantities of the components introduced into the container are calculated to provide the desired concentration of the dexamethasone phosphate in the final composition.
  • the contents of the container Upon warming to room temperature, the contents of the container attain a pressure equivalent to the vapor pressure of the mixture of the propellants employed, which serves as the driving force for the aerosolization.
  • Example 2 Dexamethasone phosphate, disodlium 0.005 Dichlorodifiuorome-tliane (Freon 12) 34.56 1,2-diehloro-1,1,2,24etrafluoroethane (Freon 114) 65.00 Sorbitan trioleate 0.435
  • Example 4 Dexamethasone phosphate, disodium r 0.001 Dichlorordifiuorome-thane (Freon l2) 34.560 1,2-dichloro-1,1,2,2-tetrafiuorethane (Freon 114) 63.439 Sorbitan t-rioleate 2.00
  • composition of this invention When the composition of this invention is utilized for inhalation therapy for asthma and other respiratory diseases there is obtained greater deposition andretention of the medicated particles in that region of the bronchial tree where it is optimally utilized so that .a mere fraction of the dose normally required by mouth or by injection need be employed.
  • the composition is organoleptically-acceptable to the patient. The-combined attributes of a reduced dosage, an acceptable taste and an e'ificient mode of administnation enables the composition of the present invention to be utilized by a greater number of patients and over a more prolonged period of time as compared to similar compositions hitherto attempted, described or made available in the art.
  • the attribute of a reduced dosage is especially important in that this markedly reduces the propensity for the development of other unwanted effects, or side effects, in the patient, as are typical of the administration of a full dose of anti-flamrnatory steroid over pnolonged periods of time.
  • clinical experience has shown that use of the present composition by inhalation'therapy permits a reduction in total steroid consumption inasthmatics byat least a factor of three and often even 'by as much as a factor of ten as compared to the usual oral dose. In chronic therapy of diseases such as asthma this becomes exceedingly important.
  • the use of the com-position as a nasal aerosol also permits use of the active anti-flammat'ory steroid in much smaller doses than would be required to produce like effects by oral administration.
  • a substantially anhydrous self-propelling dexamethasone phosphate composition suitable for inhalation aerosol therapy and capable of being-administered in sub stantially reduced dosages as compared-to other modes of administration consisting essentially of a suspension of substantially anhydrous disodium dexamethasone phosphate having a particle size in the range of from about 1 to 10 microns in a liq-ui dnontoxic propellent having a vapor pressure between about 15 and pounds per square inch gauge at 70 F. with sorbitan trioleate as a dispersing agent, the ingredients being present withinthe ranges:
  • Disodium dexamethasone phosphate 0.001 to 0.18 Sorbitan trioleate 0.01 to 2 Propellant Remainder (substantially) 2.

Description

3 282 791 INHALATION AERosbL SUSPENSION F ANHY- DROUS DISODIUM DEXAMETHASONE PHOS- PHATE, PROPELLENTS, AND SORBITAN TRI- OLEAT E Thomas J. Macek, Glenside, Pa., assignor t0 Merck & Co., Inc., Rahway, N..l., a corporation of New Jersey No Drawing. Filed Aug. 17, 1965, Ser. No. 480,509 2 Claims. (Cl. 16782) This application is a continuation-in-part of my earlier filed applications Serial No. 206,159 filed on June 29, 1962, and Serial No. 349,469 filed on March 4, 1964, both now abandoned.
This invention relates to pharmaceutical compositions, and more particularly, to self-propelling, organolepticallyacceptable aerosol compositions containing the water-soluble anti-inflammatory steroid, dexamethasone phosphate.
In many conditions, particularly those which involve the respiratory system as in asthma, bronchitis, infectious and inflammatory diseases of the respiratory tract, and even coughing andthe allergic manifestations of the common cold, proper inhalation thereapy would be exceedingly useful. Aerosol application of appropriate and effective medication would also be useful in inflammatory disorders of the nasal mucose such as allergic rhinitis, polyposis, etc.
A recent advance in the mode of administering steroids for asthma, etc. was the development of self-propelling medicament compositions. Up to now, a fully satisfactory inhalation aerosol of an anti-inflammatory steroid has not been made available for general use in medicine. Indeed, the literature even describes some such experimental aerosols as being'unacceptable to patients because of their extremely bitter taste, or because they were therapeutically ineffective.
United States Patent 0 The present invention provides a self-propelling com- 7 position of the water soluble steroid dexamethasone phosphate in a dosage of dexamethasone phosphate substantially reduced compared to the usual oral or parenteral dose and in a composition which has an agreeable and acceptable taste.
It should be substantially anhydrous and finely divided in form for inhalation therapy. The particle size of the dexamethasone phosphate should be between about 1 micron and about 10 microns, and preferably in the range of about 1 to 5 microns. It should constitute from 0.001 to 0.18% of the total composition by weight.
The self-propelling compositions of this invention include substantially anhydrous suspensions or dispersions of the solid dexamethasone phosphate disodium salt medicament uniformly dispersed or suspended throughout the nontoxic liquid propellant with the aid of a suitable dispersing agent. This dispersing agent is sorbitan trioleate (sold as Span 85) and it is employed in the range of 0.01 to 2.0% by weight of the total composition.
ice
The liquified propellant employed in the novel composition of this invention should be non-toxic and have a vapor pressure between about 15 and 70 pounds and preferably between about 20 and 30 pounds per square inch gauge at 70 F. Among the propellants having the above characteristics are the fiuorinated'or fiuorochlorinated lower saturated aliphatic hydrocarbons. The preferred propellants of this type are the halogenated alkanes containing not more than two carbon atoms and at least one fluorine atom. Illustrative of these are trichl-oromonofiuoromethane, dichloromonofluoromethane, monochlorotrifiuoromethane, dichlorodifluoromethane, monochlorotrifluoromethane, dichloromonofluoromethane, and 1,2- dichloro-1,1,2,2-tetrafluoroethane. These compounds are available commercially from E. I. du Pont de Nemours and Company under the trade name Freon, and from others under different trade names.
It will be realized that the fluorinated or fiuorochlorinated lower saturated aliphatic hydrocarbons having the above-mentioned characteristics may be employed singularly or in compatible admixtures. In addition, it will be further realized that other non-toxic propellants having a vapor pressure without the limits prescribed above may be utilized in compatible admixtures with or without one or more propellants having the required vapor pressure providing that the vapor pressure of such mixtures is within the prescribed range. This liquefied propellant constitutes substantially the entire remainder of the composition, although other ingredients amounting to as much as 1 to 2% of the total composition by'weight may be present.
In preparing the composition of this invention, the dexamethasone phosphate as the disodium salt is first ground, milled or micronized to a particle size in the range specified hereinabove. It is then dried by conventional methods to substantially remove any moisture which .may be present. A desired amount of finely divided and substantially anhydrous medicament is then suspended by means of dispersion agitation in a measured amount of the propellant or propellant mixture with the sorbitan trioleate, previously cooled to a temperature of about -25 F. The suspension is made by appropriate dilution, then without permitting the temperature of the suspension to rise above the boiling point of the propellant, the suspension is filled into a suitable container which may be metal,
glass or plastic, and the container immediately is sealed with a closure equipped with a suitable dispensing valve arrangement such as described in US. Patent 2,721,010.
The quantities of the components introduced into the container are calculated to provide the desired concentration of the dexamethasone phosphate in the final composition. Upon warming to room temperature, the contents of the container attain a pressure equivalent to the vapor pressure of the mixture of the propellants employed, which serves as the driving force for the aerosolization.
The following examples illustrate the preparation of specific compositions provided by this invention but it is understood that the invention is not to be restricted thereby to the embodiments described in these examples.
3 Example 2 Dexamethasone phosphate, disodlium 0.005 Dichlorodifiuorome-tliane (Freon 12) 34.56 1,2-diehloro-1,1,2,24etrafluoroethane (Freon 114) 65.00 Sorbitan trioleate 0.435
. 10.0.00 Example 3 Dexamethasone phosphate, disodium 0.008 Dichlorodifluo-rornethane (Freon 12) 34.5.6 1,2-dichloro-1,2,2-tetrafluoroethane (Freon 114) 65.00 Sorbitan trioleate 0.432
100.00 Example 4 Dexamethasone phosphate, disodium r 0.001 Dichlorordifiuorome-thane (Freon l2) 34.560 1,2-dichloro-1,1,2,2-tetrafiuorethane (Freon 114) 63.439 Sorbitan t-rioleate 2.00
When the composition of this invention is utilized for inhalation therapy for asthma and other respiratory diseases there is obtained greater deposition andretention of the medicated particles in that region of the bronchial tree where it is optimally utilized so that .a mere fraction of the dose normally required by mouth or by injection need be employed. In addition, the composition is organoleptically-acceptable to the patient. The-combined attributes of a reduced dosage, an acceptable taste and an e'ificient mode of administnation enables the composition of the present invention to be utilized by a greater number of patients and over a more prolonged period of time as compared to similar compositions hitherto attempted, described or made available in the art.
The attribute of a reduced dosage is especially important in that this markedly reduces the propensity for the development of other unwanted effects, or side effects, in the patient, as are typical of the administration of a full dose of anti-flamrnatory steroid over pnolonged periods of time. Indeed, clinical experience has shown that use of the present composition by inhalation'therapy permits a reduction in total steroid consumption inasthmatics byat least a factor of three and often even 'by as much as a factor of ten as compared to the usual oral dose. In chronic therapy of diseases such as asthma this becomes exceedingly important. The use of the com-position as a nasal aerosol also permits use of the active anti-flammat'ory steroid in much smaller doses than would be required to produce like effects by oral administration.
What is claimed is:
1. A substantially anhydrous self-propelling dexamethasone phosphate composition suitable for inhalation aerosol therapy and capable of being-administered in sub stantially reduced dosages as compared-to other modes of administration consisting essentially of a suspension of substantially anhydrous disodium dexamethasone phosphate having a particle size in the range of from about 1 to 10 microns in a liq-ui dnontoxic propellent having a vapor pressure between about 15 and pounds per square inch gauge at 70 F. with sorbitan trioleate as a dispersing agent, the ingredients being present withinthe ranges:
Percent by weight Disodium dexamethasone phosphate 0.001 to 0.18 Sorbitan trioleate 0.01 to 2 Propellant Remainder (substantially) 2. The composition of claim 1 in which said particle size is from about 1 to 5 microns.
References Cited by the Examiner Duvenci et al.: Dexarnethasone Therapy in Bronchial Asthma, Annals of Allergy, 17(5): 695-700 Sept.-Oct. 1959.
Falliers et al.: Dexamethasonein Childhood Asthma, Annals of Allergy, 17: 887-894, Nov.,Dec. 1959.
Franklin et al.: Aerosolized Steroids in Bronchial Asthma, J. Allergy 29(3): 214-221, May 1958.
Stresemann: The Dosage of Dexamethasone and Triamcinolone in Bronchial Asthma, Lancet II 1959: 257- 258, Sept. 5, 1959.
ELBE'RT L. ROBERTS, Primary Examiner.
SHEP K. ROSE, Assistant Examiner.

Claims (1)

1. A SUBSTANTIALLY ANHYDROUS SELF-PROPELLING DEXAMETHASONE PHOSPHATE COMPOSITION SUITABLE FOR INHALATION AEROSOL THERAPY AND CAPABLE OF BEING ADMINISTERED IN SUBSTANTIALLY REDUCED DOSAGES AS COMPARED TO OTHER MODES OF ADMINISTRATION CONSISTING ESSENTIALLY OF A SUSPENSION OF SUBSTANTIALLY ANHYDROUS DISODIUM DEXAMETHASONE PHOSPHATE HAVING PARTICLE SIZE IN THE RANGE OF FROM ABOUT 1 TO 10 MICRONS IN A LIQUI DNONTOXIC PROPELLENT HAVING A VAPOR PRESSURE BEING ABOUT 15 AND 70 POUNDS PER SQUARE INCH GAUGE AT 70*F. WITH SORBITAN TRIOLEATE AS A DISPERSING AGENT, THE INGREDIENTS BEING PRESENT WITHIN THE RANGES:
US480509A 1965-08-17 1965-08-17 Inhalation aerosol suspension of anhydrous disodium dexamethasone phosphate, propellents, and sorbitan trioleate Expired - Lifetime US3282791A (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2320111A1 (en) * 1972-04-20 1973-10-31 Allen & Hanburys Ltd SOLVATED, CRYSTALLINE, ANTI-INFLAMMATORY STEROIDS, METHODS FOR THEIR PRODUCTION AND AEROSOL FORMULATIONS CONTAINING THESE MATERIALS
DE2703119A1 (en) * 1976-01-30 1977-08-04 Fisons Ltd SODIUMCROMOGLYCAT WITH LESS THAN 5% WATER AND THIS COMPREHENSIVE PHARMACEUTICAL PREPARATIONS
DE2624924A1 (en) 1975-05-27 1977-12-15 Syntex Inc FLUNISOLIDE AND THEIR PHARMACEUTICAL USE
US4405598A (en) * 1976-01-30 1983-09-20 Fisons, Limited Composition for treating asthma
US4933168A (en) * 1975-05-27 1990-06-12 Syntex Pharmaceuticals International Limited Stable, crystalline flunisolide
EP0627222A1 (en) * 1993-06-03 1994-12-07 MERCK PATENT GmbH Infusion and injection compositions containing dexamethasone-21-phosphate-disodium salt and polysorbate
US20110245217A1 (en) * 2010-04-06 2011-10-06 The Children's Research Institute Methods for diagnosing and treating asthma
US9861642B2 (en) 2010-04-06 2018-01-09 The Children's Research Institute Methods for diagnosing and treating asthma

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2779775A (en) * 1954-09-30 1957-01-29 Merck & Co Inc Phosphate derivatives of 9alpha-fluorosteroids
CA544990A (en) * 1957-08-20 M. Andrews Alvadore Apparatus for perforating sheet material
US2936313A (en) * 1957-11-19 1960-05-10 Glaxo Lab Ltd Preparation of steroidal 21-phosphate derivatives
US3014844A (en) * 1957-01-31 1961-12-26 Riker Laboratories Inc Self-propelling powder dispensing compositions
US3045033A (en) * 1961-05-10 1962-07-17 Schering Corp Water soluble cyclophosphate esters of steroids and process for preparing same
US3056812A (en) * 1958-08-08 1962-10-02 Glaxo Lab Ltd Steroid 21-pyrophosphate esters
US3073816A (en) * 1959-11-26 1963-01-15 Merck Ag E Process of producing 21-orthophosphates of steroids and the 21-diamide orthophosphate intermediates therefor
US3073743A (en) * 1959-07-30 1963-01-15 Upjohn Co Antiinflammatory steroid acetonide compositions and therapy
US3138527A (en) * 1961-01-16 1964-06-23 Upjohn Co Topical anti-inflammatory process
US3219533A (en) * 1962-11-29 1965-11-23 Merck & Co Inc Aerosol solid medicament in propellant and low-level ethanol avoiding higher-level ethanol dispersed-solid reflocculation

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA544990A (en) * 1957-08-20 M. Andrews Alvadore Apparatus for perforating sheet material
US2779775A (en) * 1954-09-30 1957-01-29 Merck & Co Inc Phosphate derivatives of 9alpha-fluorosteroids
US3014844A (en) * 1957-01-31 1961-12-26 Riker Laboratories Inc Self-propelling powder dispensing compositions
US2936313A (en) * 1957-11-19 1960-05-10 Glaxo Lab Ltd Preparation of steroidal 21-phosphate derivatives
US3056812A (en) * 1958-08-08 1962-10-02 Glaxo Lab Ltd Steroid 21-pyrophosphate esters
US3073743A (en) * 1959-07-30 1963-01-15 Upjohn Co Antiinflammatory steroid acetonide compositions and therapy
US3073816A (en) * 1959-11-26 1963-01-15 Merck Ag E Process of producing 21-orthophosphates of steroids and the 21-diamide orthophosphate intermediates therefor
US3138527A (en) * 1961-01-16 1964-06-23 Upjohn Co Topical anti-inflammatory process
US3045033A (en) * 1961-05-10 1962-07-17 Schering Corp Water soluble cyclophosphate esters of steroids and process for preparing same
US3219533A (en) * 1962-11-29 1965-11-23 Merck & Co Inc Aerosol solid medicament in propellant and low-level ethanol avoiding higher-level ethanol dispersed-solid reflocculation

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2320111A1 (en) * 1972-04-20 1973-10-31 Allen & Hanburys Ltd SOLVATED, CRYSTALLINE, ANTI-INFLAMMATORY STEROIDS, METHODS FOR THEIR PRODUCTION AND AEROSOL FORMULATIONS CONTAINING THESE MATERIALS
DE2624924A1 (en) 1975-05-27 1977-12-15 Syntex Inc FLUNISOLIDE AND THEIR PHARMACEUTICAL USE
DE2661037C2 (en) * 1975-05-27 1989-04-06 Syntex (U.S.A.) Inc., Palo Alto, Calif., Us
US4933168A (en) * 1975-05-27 1990-06-12 Syntex Pharmaceuticals International Limited Stable, crystalline flunisolide
DE2703119A1 (en) * 1976-01-30 1977-08-04 Fisons Ltd SODIUMCROMOGLYCAT WITH LESS THAN 5% WATER AND THIS COMPREHENSIVE PHARMACEUTICAL PREPARATIONS
US4405598A (en) * 1976-01-30 1983-09-20 Fisons, Limited Composition for treating asthma
EP0627222A1 (en) * 1993-06-03 1994-12-07 MERCK PATENT GmbH Infusion and injection compositions containing dexamethasone-21-phosphate-disodium salt and polysorbate
US20110245217A1 (en) * 2010-04-06 2011-10-06 The Children's Research Institute Methods for diagnosing and treating asthma
US9188581B2 (en) * 2010-04-06 2015-11-17 The Children's Research Instiute Methods for diagnosing and treating asthma
US9861642B2 (en) 2010-04-06 2018-01-09 The Children's Research Institute Methods for diagnosing and treating asthma

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