Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS3095355 A
Publication typeGrant
Publication dateJun 25, 1963
Filing dateOct 12, 1961
Priority dateOct 12, 1961
Publication numberUS 3095355 A, US 3095355A, US-A-3095355, US3095355 A, US3095355A
InventorsBernard Abramson, Greif Norman L, Silson John E
Original AssigneeRevlon
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Aerosol composition
US 3095355 A
Abstract  available in
Images(3)
Previous page
Next page
Claims  available in
Description  (OCR text may contain errors)

United States Patent AEROSOL COMPOSITION Bernard Abramson, White Plains, Norman L. Greif, Howard Beach, and John E. Silson, Pleasantville, N.Y., assignors to Revlon, Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Oct. 12, 1961, Ser. No. 147,402

' 8 Claims. (Cl. 167-54) This invention relates to improved self-propelling compositions containing dispersed medica-ments for inhalation therapy, and to methods of making and using the same.

It has already been proposed in the art that selfpropelling compositions containing medicaments and adaptable to administration of the medicament in aerosol form be employed for inhalation therapy. United States Patent No. 2,868,691, granted January 13, 1959, to Porush et al., describes in detail a number of such medicament containing compositions. In particular, the patent describes self-propelling compositions in which bronchodilator amines and/or their acid-addition salts are dissolved in a non-toxic liquid propellant composition with a liquid co-solvent which assists in dissolving the medicament in the liquefied propellant. According to the patent, the co-solvent constitutes between about percent or 10 percent and 40 percent, preferably between about percent and 40 percent, by weight of the total composition.

A significant disadvantage of such prior art compositions is that the size of the aerosol particle reaching the lungs is too large to permit medically effective distribution of the dissolved drugs, particularly the vasoconstrictors, to those bronchioles of very narrow diameter. In an aerosol composition used for inhalation therapy, it is highly desirable that the aerosol particles have a particle size less than about 10 microns, and preferably less than 3 or 5 microns, such as between 0.5 and 3 microns. With the aerosol-dispersing valves now available in the art, it is not possible to dispense aerosol particles of such fine diameter. Present-day valves, on the contrary, distribute aerosol particles having a diameter of about 35-40 microns. Since these aerosol particles, on leaving the aerosol valve, contain a high proportion of volatile ingredients, i.e. the propellant, the drop size of the aerosol decreases as these volatile materials evaporate, and the size of the particles reaching the lungs is in large part determined by the proportion of non-volatile ingredients in the aerosol composition.

Prior .art aerosol compositions, such as those shown in Patent 2,868,691, which contain a large proportion of a relatively involatile co-solvent material such as ethanol, cannot attain by evaporation the desirable small particle size required for maximally effective physiological distribution of the drug in the lungs.

According to the present invention, the small aerosol particle size desired for effective distribution of a medicament in the lungs is obtained by employing self-propelling compositions containing the drugs in micronized form dis- I persed, rather than dissolved, in a propellant composition.

Effective dispersion of the finely divided drug particles in the propellant is accomplished with the use of very small quantities of a suspending agent, present as a coating on the micronized drug particles. Evaporation of the propellant from the aerosol particles after spraying from the aerosol container leaves finely divided drug particles coated with a fine film of the suspending agent. Since the particles themselves are extremely finely divided for incorporation into the aerosol composition, and since the quantity of relatively non-volatile suspending agent employed is very small, the average diameter of the coated particles after evaporation of the volatile propellant there- 3,095,355. Patented June 25, 1963 from is still quite small and falls easily within the particle size range of less than 10 microns desired for effective distribution of the drug to the bronchioles.

Although many drugs insoluble in typical non-toxic propellant compositions can be dispensed in the manner suggested by the invention, the inventionis particularly well-adapted to the dispensing of such antiasthmatic bronchodilator amines as epinephrine and isoproterenol. These materials are generally employed medicinally in the form of water-soluble salts formed by combination of an organic or inorganic acid with these amines. Thus, epinephrine, in its levo or racemic form, can be employed as the chloride, the bitartrate, or the ascorbate, for example. Similarly, isoproterenol may be employed in the form of the sulfate or hydrochloride, etc. ployed according to the invention in finely divided or micronized form in which the average particle size is less than about 5 microns.

The solid drugs are dispersed in a nontoxic propellant composition employing a fatty alcohol as a dispersing agent. In particular, oleyl alcohol, alone or in admixture with other saturated and unsaturated fatty alcohols having 12 to 22 carbon atoms, preferably from 14 to 18 carbon atoms, is employed as the suspending agent.

A minimum quantity of suspending agent sufiicient to bring about effective dispersion of the solid drug particles in the propellant composition is employed, and varies with the amount of solid drug to be suspended. For the anti-asthmatic drugs mentioned earlier, minimal quantitles of about 0.1 to 0.2 percent by weight of suspending agent, based on the weight of the composition, are employed. Although relatively large amounts of the sus pending agent in the self-propelling composition of the invention are not disturbing to the maintenance of dispersion, and are not physiologically harmful, a minimum quantity of dispersing agent.is...preferably employed since the thickness of the coating of the relatively non-volatile dispersing agent on the micronized drug particles will be determinative of the size of the particles reaching the lungs after evaporation of the volatile propellants therefrom. To maintain an upper particle size limit less than 10 microns, preferably less than 5 microns, quantities of dispersing agent less than about 4 percent by weight of the total composition are suitably employed. Particularly good compositions, from the point of view of particle size, have been obtained using between about 0.5 and about 1 percent by weight of the dispersing agent in the self-propelling composition. It will be seen that this quantity of non-volatile dispersing agent is relatively small compared with even the minimum amount of a cosolvent required in the prior art for solution of a drug in a volatile propellant.

These quantities of suspending or dispersing agent are sufiicient for the quantity of drug normally dispersed in a volatile propellant. In general, the drug is dis persed in amounts varying between about 0.1 percent and about 2 percent by weight of the volatile propellant, preferably in amounts varying between 0.15 percent and 0.5 percent by weight of the propellant.

Suitable non-toxic volatile liquid propellants are known in the art, and are discussed in Patent 2,868,691 for example. These materials are generally fluorinated or fiuorochlorinated lower saturated aliphatic hydrocarbons, suitably halogenated lower alkanes containing one to four carbon atoms, preferably one or two carbon atoms, and at least one fluorine atom. Any of the materials disclosed in the earlier mentioned patent can be employed in the present invention, including propellants such as dichlorodifluoromethane (Freon l2), dichlorotetrafluonoethane (Freon 114), and trichloromonofluorornethane (Freon 11). These propellants, or suitable mixtures thereof, will produce a propellant vapor These drugs are em pressure between about 25 and about 60 pounds per square inch at room temperatures (20-25 C.). Suitable mitxures of the propellants can be employed to give a preferred vapor pressure between about 35 and about 40 pounds per square inch at these temperatures. For unknown reasons, the presence of trichloromonofiuoromethane (Freon 11) seems to increase the dispersibility of solid particles in the volatile propellant mixture. However, the vapor pressure of this Freon is rather low, and suitable propellant compositions are prepared by mixing other of the Freons having higher vapor pressures with Freon 11." The best propellant compositions contain about 20 percent by weight of Freon 11, blended with Freon 12 and/or Freon 114. A volatile propellant composition containing about 20 percent of Freon 11, about 30-35 percent by weight of Freon 114, and between about 45 and 50 percent by weight of Freon 12 shows particularly good suspending and pressure qualities. However, this mixture and other specific mixtures are not critical to the invention, and any non-toxic liquid volatile propellant such as those earlier described herein may be employed.

Preparation of the self-propelling compositions of the invention proceeds by intimately mixing appropriate quantities of the anti-asthmatic drugs earlier mentioned, preferably in salt form, with oleyl alcohol or mixtures of oleyl alcohol with one or more fatty alcohols having between 12 and 22 carbon atoms, such as lauryl, myristyl, stearyl, cetyl, linoleyl, or behenyl alcohols. It is desired to produce an intimate mixture of the drug and suspending agent in a free flowing form containing a minimum of the suspending agent. In general, this is accomplished by mixing up to 2 parts of the finely divided drug with 1 part of suspending agent, although larger quantities of the drug can be used providing that the drug particles become suitably covered with the suspending agent. Inadequate coverage of the drug particles with the suspending agent is usually indicated by the formation of a very thick, unworkable paste, and if such pastes are formed, additional alcohol is added until a free-flowing composition or slurry is obtained. For complete dispersion, the resulting mixture is usually apssed through a colloid mill. Mixtures with particularly good flow properties contain about 60 percent by weight of suspending agent, the balance being the drug.

The resulting slurry is then metered into aerosol containers, and the non-toxic volatile propellant is then added either by conventional cold fill methods, in which the propellant is chilled to a temperature of about 40 C., or is introduced into the containers at room temperature under pressure. The components of the non-toxic propellant mixture can be added individually or in combination.

Although oleyl alcohol alone is an extremely satisfactory suspending agent, the material is a very mobile fluid. If used in large amounts with a micronized drug, the drug may settle in the pre-mixed drug-alcohol compositions. Such settling might interfere with proper metering of the drug-alcohol mixture into the aerosol containers. In such a case, the other alcohols, which are solids at room temperature, may be added to oleyl alcohol to increase its viscosity. In general, mixtures containing up to equal portions of oleyl alcohol and one or more of the other fatty alcohols mentioned can be employed. Mixtures containing relatively large amounts of the solid alcohols may be viscous or pasty solids at room temperatures, but can be metered well into the dosage containers at slightly elevated temperatures.

The products of the invention are conveniently used in aerosol containers having a metered valve which dispenses a controlled quantity of the self-propelling aerosol composition as a single dose. These containers are Well known in the art, and may be made of any materials, such as glass, plastic, or metal adequate to contain the pressures generated by the volatile propellant materials the-rein.

4 Conventionally, these metered containers operate by inversion of the container to fill a well of predetermined volume with the self-propelling composition. On activation of the aerosol valve, only this predetermined volume of self-propelling composition is dispersed as an aerosol. Normal handling of an aerosol container, and particularly the manipulation usually performed with a metered aerosol container, causes agitation of container contends sufficient to redisperse any particles which may have settled.

A better understanding of the present invention and of its many advantages can be had by referring to the following examples, given by way of illustration.-

Example A number of free-flowing mixtures containing :1 micronized drug having a particle size of less than about 5 microns and a fatty alcohol suspending agent were prepared by mixing the following components together in suitable mixing apparatus such as a propeller type-mixer.

Drug and suspending agent: Parts by weight Epinephrine hydrochloride 2 Oleyl alcohol 3 Epinephrine hydrochloride 1 Oleyl alcohol 4 (III) Isoproterenol sulfate 2 Oleyl alcohol 3 Isoproterenol sulfate l Oleyl alcohol 4 Epinephrine hydrochloride l Oleyl alcohol 2 Myristyl alcohol 1 Epinephrine hydrochloride 1 Oleyl alcohol 4 Stearyl alcohol 1 (VII) Epinephrine hydrochloride l Oleyl alcohol 4 Cetyl alcohol 1 (VIII) Isoproterenol sulfate 1 Oleyl alcohol 1 Myristyl alcohol 1 These mixtures, hereinafter referred to as concentrates, were used to formulate self-propelling compositions by admixture with suitably non-toxic volatile liquid propellants in the following proportions:

illustrative and are not limiting on the scope and spirit of the invention.

What is claimed is:

1. A composition adaptable to use in aerosol form for inhalation therapy and comprising finely divided particles of a water-soluble acid addition salt of a member of the group consisting of epinephrine and isoproterenol dispersed in "a non-toxic liquid propellant, said particles being coated With-a dispersing agent selected from the group consisting of oleyl alcohol and mixtures of oleyl alcohol with other fatty alcohols having from 12 to 22 carbon atoms.

2. A composition as in claim 1 wherein said dispersing agent is oleyl alcohol.

3. A composition adaptable to use in aerosol form for inhalation therapy and comprising .a liquid non-toxic halogenated lower alkane propellant, about 0.1 to about 2 percent, by weight of said propellant, of finely divided particles of a water-soluble acid addition salt of a member of the group consisting of epinephrine and isoproterenol dispersed in said propellant, and from about 0.1 to about 4 percent, by weight of the composition, of a dispersing agent selected from the group consisting of oleyl alcohol and mixtures of oleyl alcohol with other fatty alcohols having from 12 to 22 carbon atoms, the dispersing agent being present as a coating on said particles.

4. A composition as in claim 3 wherein said dispersing agent is oleyl alcohol. 1

5. A composition as in claim 3 wherein said propellant composition has a vapor pressure between about and about pounds per square inch at 205-25 C.

6. A composition as in claim 3 wherein said propellant composition consists essentially of a mixture of dichlorodifluoromethane, dichlorotetrafiuoroethane, and trichloromonofluoromethane.

7. A composition as in claim 3 wherein said watersoluble addition salt is epinephrine hydrochloride.

8. A composition as in claim 3 wherein said watersoluble addition salt is isoproterenol sulfate. 7

References Cited in the file of this patent UNITED STATES PATENTS s Thiel Dec. 26, 1961 OTHER REFERENCES

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3014844 *Jan 3, 1958Dec 26, 1961Riker Laboratories IncSelf-propelling powder dispensing compositions
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3304230 *Feb 18, 1963Feb 14, 1967RevlonLiquid aerosol propellant solutions of fatty acid salts of physiologically active amines
US3968203 *Aug 26, 1969Jul 6, 1976Jerome G. SpitzerAerosol astringent composition
US4352789 *Mar 17, 1980Oct 5, 1982Minnesota Mining And Manufacturing CompanyAerosol compositions containing finely divided solid materials
US5292884 *Oct 13, 1992Mar 8, 1994Biomide Investment Limited PartnershipCyclic hydroxamic acids
US5514713 *Dec 2, 1994May 7, 1996Ono Pharmaceutical Co., Ltd.Amidinophenol derivatives
US5534536 *Aug 23, 1994Jul 9, 1996Ono Pharmaceuticals Co. Ltd.Fused phenol derivatives
US5750544 *Apr 19, 1996May 12, 1998Ono Pharmaceuticals Co., Ltd.Fused phenol derivatives
US5861268 *May 23, 1996Jan 19, 1999Biomide Investment Limited PartnershipMethod for induction of tumor cell apoptosis with chemical inhibitors targeted to 12-lipoxygenase
US6022893 *Aug 7, 1996Feb 8, 2000Ono Pharmaceutical Co., Ltd.Hydroxamic acid derivatives
US7160538Sep 3, 2004Jan 9, 2007Boehringer Ingelheim KgSuspension aerosol formulations of pharmaceutical products
US7176240Jul 15, 2002Feb 13, 2007Ono Pharmaceutical Co., Ltd.Pentanoic acid derivatives
US7569608Jul 29, 2005Aug 4, 2009Ono Pharmaceutical Co., Ltd.Pentanoic acid derivatives
US7569609Jul 29, 2005Aug 4, 2009Ono Pharmaceutical Co., Ltd.Pentanoic acid derivatives
US7947742Jun 26, 2003May 24, 2011Civitas Therapeutics, Inc.Inhalable epinephrine
US8597616Oct 22, 2008Dec 3, 2013Board Of Regents Of The University Of Texas SystemDry powder drug delivery formulations, methods of use, and devices therefore
US8722340Oct 18, 2007May 13, 2014Board Of Regents, The University Of Texas SystemJAB1 as a prognostic marker and a therapeutic target for human cancer
US8853277Nov 30, 2010Oct 7, 2014The United States Of America, As Represented By The Secretary, Department Of Health And Human ServicesNitroxide therapy for the treatment of von Hippel—Lindau disease (VHL) and renal clear cell carcinoma (RCC)
US20030096802 *Jul 15, 2002May 22, 2003Ono Pharmaceutical Co., Ltd.Pentanoic acid derivatives
US20040076588 *Jun 26, 2003Apr 22, 2004Batycky Richard P.Inhalable epinephrine
US20040184993 *Jan 30, 2004Sep 23, 2004Chiesi Farmaceutici S.P.A.Pharmaceutical aerosol composition containing HFA 227 and HFA 134a
US20050031548 *Sep 3, 2004Feb 10, 2005Boehringer Ingelheim KgSuspension aerosol formulations of pharmaceutical products
US20050261371 *Jul 29, 2005Nov 24, 2005Ono Pharmaceutical Co., Ltd.Pentanoic acid derivatives
US20050267167 *Jul 29, 2005Dec 1, 2005Ono Pharmaceutical Co., Ltd.Pentanoic acid derivatives
US20050267168 *Jul 29, 2005Dec 1, 2005Ono Pharmaceutical Co., Ltd.Pentanoic acid derivatives
US20060128810 *Oct 9, 2003Jun 15, 2006Kyoto UniversityRemedies for allergic diseases
US20070021323 *Sep 21, 2006Jan 25, 2007Government of the USA, represented by the Secretary,Use of a nitroxide or a prodrug thereof in the prophylactic and therapeutic treatment of cancer
US20090104127 *Jul 25, 2008Apr 23, 2009Boehringer Ingelheim KgSuspension aerosol formulations of pharmaceutical products
US20090191134 *Jun 12, 2007Jul 30, 2009Medispray Laboratoriespvt. Ltd.Stable aerosol pharmaceutical formulations
US20100092402 *Jan 25, 2008Apr 15, 2010Mucokinetica Ltd.Treatment of respiratory disease
US20110014134 *Sep 27, 2010Jan 20, 2011Boehringer Ingelheim KgSuspension aerosol formulations of pharmaceutical products
EP0703216A1Sep 19, 1995Mar 27, 1996Ono Pharmaceutical Co., Ltd.Amidinophenol derivatives as protease inhibitors
EP0757037A2Jul 29, 1996Feb 5, 1997Ono Pharmaceutical Co., Ltd.Sulfonylamino acid derivatives as metalloproteinase inhibitors
EP2206698A1Dec 21, 2009Jul 14, 2010ONO Pharmaceutical Co., Ltd.Ethynylindole compounds
EP2243493A1Jul 2, 2003Oct 27, 2010Ono Pharmaceutical Co., Ltd.Immunopotentiative composition
EP2253642A1Dec 25, 1998Nov 24, 2010ONO Pharmaceutical Co., Ltd.Polypeptides, cDNAs encoding the same and utilization thereof
EP2255829A2Jul 22, 2002Dec 1, 2010Ono Pharmaceutical Co., Ltd.Pharmaceutical composition for treatment of diseases associated with decrease in bone mass comprising EP4 agonist as active ingredient
EP2264059A1Dec 25, 1998Dec 22, 2010ONO Pharmaceutical Co., Ltd.Polypeptides, cDNAs encoding the same and utilization thereof
EP2270051A2Jan 22, 2004Jan 5, 2011Ono Pharmaceutical Co., Ltd.Antibody specific for human PD-1 and CD3
EP2281818A1Feb 18, 2003Feb 9, 2011Ono Pharmaceutical Co., Ltd.Fused pyridazine derivative compounds and drugs containing these compounds as the active ingredient
EP2308562A2Dec 24, 2004Apr 13, 2011Ono Pharmaceutical Co., Ltd.Azetidine ring compounds and drugs comprising the same
EP2364982A1Apr 16, 2004Sep 14, 2011ONO Pharmaceutical Co., Ltd.Spiro-piperidine compounds as chemokine receptor antagonists and medicinal use thereof
EP2385040A1Mar 12, 2004Nov 9, 2011ONO Pharmaceutical Co., Ltd.Nitrogen-containing heterocyclic derivatives and drugs containing the same as the active ingredient
EP2422814A1Jul 23, 2004Feb 29, 2012Ono Pharmaceutical Co., Ltd.Remedy for cartilage-related diseases
EP2465537A1Oct 9, 2003Jun 20, 2012ONO Pharmaceutical Co., Ltd.Microspheres comprising ONO-1301
EP2465538A2Oct 20, 2005Jun 20, 2012Ono Pharmaceutical Co., Ltd.Use of immunesuppressant receptor
EP2481732A1Aug 31, 2004Aug 1, 2012Ono Pharmaceutical Co., Ltd.Condensed ring compound and use thereof
EP2508204A2Jun 25, 2003Oct 10, 2012Ono Pharmaceutical Co., Ltd.Remedies for diseases caused by vascular contraction or dilation
EP2565178A1May 28, 2003Mar 6, 2013Ono Pharmaceutical Co., Ltd.LPA Receptor Antagonists
EP2657235A1Oct 27, 2006Oct 30, 2013Ono Pharmaceutical Co., Ltd.Compound containing basic group and use thereof
EP2883865A1Aug 27, 2004Jun 17, 2015Ono Pharmaceutical Co., Ltd.Compound capable of binding S1P receptor and pharmaceutical use thereof
EP3002285A1Jul 5, 2011Apr 6, 2016ONO Pharmaceutical Co., Ltd.Tetrahydrocarboline derivative
WO2004002551A2 *Jun 26, 2003Jan 8, 2004Advanced Inhalation Research, Inc.Inhalable epinephrine
WO2004002551A3 *Jun 26, 2003Aug 12, 2004Advanced Inhalation Res IncInhalable epinephrine
WO2004031118A1May 28, 2003Apr 15, 2004Ono Pharmaceutical Co., Ltd.Lpa receptor antagonists
WO2004032965A1Oct 9, 2003Apr 22, 2004Ono Pharmaceutical Co., Ltd.Endogenous repair factor production promoters
WO2005063704A1Dec 24, 2004Jul 14, 2005Ono Pharmaceutical Co., Ltd.Azetidine ring compounds and drugs comprising the same
WO2007049771A1Oct 27, 2006May 3, 2007Ono Pharmaceutical Co., Ltd.Compound containing basic group and use thereof
WO2007069565A1Dec 11, 2006Jun 21, 2007Ono Pharmaceutical Co., Ltd.Bicyclic heterocyclic compound
WO2007069671A1Dec 14, 2006Jun 21, 2007Ono Pharmaceutical Co., Ltd.Bicyclic heterocyclic compound
WO2008136377A1Apr 25, 2008Nov 13, 2008Ono Pharmaceutical Co., Ltd.Bicyclic heterocyclic compound
WO2009088553A1 *Oct 22, 2008Jul 16, 2009Board Of Regents, The University Of Texas SystemDry powder drug delivery formulations, methods of use, and devices therefore
WO2010147133A1Jun 16, 2010Dec 23, 2010Ono Pharmaceutical Co., Ltd.Novel imidazopyridine compound
WO2011066537A1Nov 30, 2010Jun 3, 2011The United States Of America, As Represented By The Secretary, Department Of Health And Human ServicesNitroxide therapy for the treatment of von hippel - lindau disease (vhl) and renal clear cell carcinoma (rcc)
WO2011162222A1Jun 20, 2011Dec 29, 2011Ono Pharmaceutical Co., Ltd.Novel crystalline forms of 4,4'-[4-fluoro-7-({4-[4-(3-fluoro-2-methylphenyl)butoxy]phenyl}ethynyl)-2-methyl-1h-indole-1,3-diyl]dibutanoic acid, 4,4'-[2-methyl-7-({4-[4-(pentafluorophenyl)butoxy]phenyl}ethynyl)-1h-indole-1,3-diyl]dibutanoic acid, and 4,4'-[4-fluoro-2-methyl-7-({4-[4-(2,3,4,6-tetrafluorophenyl)butoxy]phenyl}ethynyl)-1h-indole-1,3-diyl]dibutanoic acid
WO2012074069A1Dec 1, 2011Jun 7, 2012Ono Pharmaceutical Co., Ltd.Novel compound and medical use thereof
WO2012127885A1Jan 5, 2012Sep 27, 2012Ono Pharmaceutical Co., Ltd.Tetrahydrocarboline derivative
WO2014129431A1Feb 18, 2014Aug 28, 2014Ono Pharmaceutical Co., Ltd.Trk-INHIBITING COMPOUND
Classifications
U.S. Classification424/498, 424/46, 514/653
International ClassificationA61K31/135, A61M15/00, A61K31/16, A61K9/00
Cooperative ClassificationA61K31/135, A61K9/008, A61M15/009
European ClassificationA61M15/00P, A61K9/00M20B6, A61K31/135