US2989437A - Anti-inflammatory and anti-bacterial decongestant nasal spray compositions - Google Patents

Anti-inflammatory and anti-bacterial decongestant nasal spray compositions Download PDF

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US2989437A
US2989437A US514132A US51413255A US2989437A US 2989437 A US2989437 A US 2989437A US 514132 A US514132 A US 514132A US 51413255 A US51413255 A US 51413255A US 2989437 A US2989437 A US 2989437A
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inflammatory
phenylephrine
neomycin
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Wruble Milton
Harold F Hailman
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Pharmacia and Upjohn Co
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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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/0043—Nose

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  • This invention relates to a therapeutic composition, more particularly a nasal preparation containing neomycin, an anti-inflammatory corticosteroid and phenylephrine.
  • the mucous membrane of the major portion of the nasal cavity is composed of the superficial ciliated columnar epithelium containing the terminal portion of the ducts from secretory mucous and serous glands, the basement membrane which is a band of collagen material of variable thickness underlying the ciliated epithelium, and the submucosa lying immediately under the basement membrane which is composed of connective tissue containing the mucous and serous glands, a network of blood vessels, nerves and lymphatics. This region is the predominant site of inflammatory reactions. 1
  • a thin mucous film normally covers the exposed ciliated epithelium.
  • the cilia moving rhythmically cause the mucous film to flow backward to the pharynx to remove foreign matter including bacteria.
  • the intact normally functioning nasal mucosa is on the whole quite resistant to infection.
  • a number of factors may be implicated in the disruption of physiological integrity of the nasal mucosa. Sudden exposure to change in temperature and humidity, sensitivity to allergens (pollens, molds, bacteria), overexposure to irritants such as chemicals and smoke may contribute to changes in the mucosa and result in inflammation.
  • the picture is one of vascular congestion, edema, exudation and secretory dysfunction. These changes constitute a break in the integrity of the mucosa and predispose, to infection.
  • Chronic inflammation produces several types of pathological changes in the nasal mucosa. Long standing edema or repeated allergic reactions favor polyp formation. 'It becomes evident that prompt suppression of inflammation will not only provide the patient with welcome relief but may also prevent complications.
  • -It is therefore an object of this invention to provide a therapeutic composition which iseffective in the treatment of nasal disorders. It is also an object of this invention to provide such a composition which provides a combination of active ingredients each of which enhances and supplements the activity of the other. A further object is the provision of such a preparation which reduces local edema in certain nasal conditions and thus improves the therapeutic action of the anti-inflammatory corticosteroid and/or neomycin. A still further object is the provision of such a composition which has greater antibiotic activity than neomycin alone. A further object is the provision of a combination which interferes less with cilial action than the individual components.
  • Another object is the provision of such a composition which prolongs, increases, or otherwise improves the anti-inflammatory effect of the corticosteroid.
  • a still further object is the provision of such a composition which improves the vasoconstrictor action of the phenylephrine by reducing its destruction by enzymes in the nasal mucosa.
  • a still further object is the provision of such a composition which improves the spreadr ing and local tissue penetration of the anti-inflammatory. corticosteroid when applied topically.
  • a still further object is the provision of such a composition which sup- A still which this invention pertains.
  • a therapeutic composition comprising neomycin, an anti-inflammatory corticosteroid and phenylephrine as the essential active ingredients, in a sprayable emulsion-type vehicle, preferably containing diethylaminoethyl oleyl amide phosphate.
  • composition of the present invention is prepared by dispersing the active ingredients in a vehicle suitable for nasal use.
  • vehicle be a very thin, mobile, sprayable emulsion which holds the active ingredients particularly hydrocortisone, adequately suspended for long periods of time without loss in potency and without discoloration and in which even where some settling does occur after long periods of standing, resuspension is readily attained by slight shaking.
  • anti-inflammatory corticosteroid means those adrenal cortical steroids and their derivatives which possess local anti-in flammatory activity, particularly on the mucous membranes.
  • corticosteroids include hydrocortisone (the preferred corticosteroid), cortisone, 9a-flu01O-1lfi, 17a dihydroxyprogesterone, 9oz fiuoro 11 keto-17ahydroxyprogesterone and the like.
  • hydrocortisone as used in the present specification means 17a-hydroxycorticosterone and its topically active derivatives, such as the 2l-esters including the acetate, the cyclopentylpropionate, and the like; the A analogs, such as 11B,l7u,21-trihydroxy-1,4-pregnadiene- 3,20-dione and its esters; the Z-methyl derivatives such as 2 methyl 1lfi,17a,2l tn'hydroxy 4 pregnene 3,20- dione and its esters; combinations of the foregoing derivatives, such as 2-methyl-11,9,17a,21-trihydroxy-1,4-pregna diene-3,20-dione and its esters; and the like.
  • the 2- methyl derivatives and processes for their production are disclosed in copending application Serial Number 485,318, filed January 31, 1955, now Patent No. 2,923,720. 7
  • cortisone as used in the present specification means 17a-hydroxy-1l-dehydrocorticosterone and its topically active derivatives, such as the 2l-esters including Patented June 20, 1 1;
  • a still further object is the the acetate, the hemisuccinates, and the like; the A analogs, such as 17a,21-dihydroxy-1,4-pregnadiene-3,ll, 20-trione and its esters; and the like.
  • neomycin as used in the present specification means the antibiotic more fully described in Walesman, Neomycin, Rutgers University Press, 1953. it includes the various forms of neomycin (such as the B and C forms) and their therapeutically active derivatives (such as the sulfate and the hydrochloride salts).
  • phenylephrine as used in the present specification means 1 m hydroxy-ot-(methylaminomethyl)- benzyl alcohol and its therapeutically active salts (such as the hydrochloride salt).
  • the compound is more particularly described in U.S. Patents 1,932,347 and 1,954,389.
  • the composition of the present invention is prepared as a nasal spray in a buffered, isotonic base having a pH which is most advantageous for use on the nasal mucosa (a pH between about 5.5 and 6.5).
  • the preparation must be nonirritating to the nasal mucosa.
  • the vehicle for the active ingredients is preferably an oil-in-water emulsion.
  • the emulsion is stabilized by an emulsifying or stabilizing agent, or combination of such agents, which prevents the oil globules from coalescing for long periods of time.
  • the oil or fat phase in the preferred embodiment of the present invention comprises glyceryl monostearate and spermaeeti.
  • the emulsifying agent in the preferred embodiment comprises polysorbate 80, U.S.P., and diethylaminoethyl oleyl amide phosphate.
  • the diethylaminoethyl oleyl amide phosphate performs a dual function in that it also stabilizes the phenylephrine in the nasal mucosa by reducing enzyme oxidation thereof. This stabilization function applies both to the situation where phenylephrine is used alone as well as to one in which an anti-inflammatory corticosteroid and neomycin are also present in the composition.
  • the emulsion is preferably made isotonic using such materials as sodium chloride and/or sodium citrate.
  • the latter also acts as a buffer to stabilize the pH.
  • the emulsion is preferably preserved with myristyl gamma picolinium chloride and/or sorbic acid.
  • a humectant, preferably propylene glycol, is also desirable; this material also aids in stabilizing the emulsion.
  • the combination of ingredients in the preferred embodiment of the present invention provides a composition possessing superior therapeutic and pharmaceutical properties.
  • the concentrations of the various active ingredients are important, particularly in the preferred embodiments of present invention.
  • the amounts of the active ingredients used depend primarily upon the therapeutic activity of each ingredient.
  • the concentrations of the corticosteroid used would preferably vary from 0.05 percent for Z-methyl-l 1B,17a,21-trihydroxy-1,4-pregnadiene- 3,20-dione to 2.5 percent for hydrocortisone acetate. (All percentages are weight by volume unless otherwise specified.)
  • An adequate concentration of neomycin is about 0.5 percent, although it is preferred to use an additional 0.1 percent to compensate for losses during manufacture and storage. There can be considerable variation of this amount without impairing the therapeutic effectiveness of the combination.
  • the concentration of phenylephrine preferably varies from 0.1 percent to one percent, especially 0.25 percent.
  • concentration of the fat or oil in the emulsion preferably ranges from two to four percent. Of the total composition 0.03 to 0.3 percent is preferably diethylaminoethyl oleyl amide phosphate.
  • concentration of polysorbate 80 U.S.P. in the emulsion ranges from 0.25 to 1.5 percent, preferably 0.5 percent. Although considerable variation of these concentrations is possible, the best results are obtained within the preferred limits given.
  • the micronized corticosteroid can be dispersed in the aqueous phase before the emulsification step.
  • the 4 corticosteroid shows some decomposition at the emulsification temperature it is preferably dispersed in the emulsion after it is cooled either before, or at the same time as, the addition of the phenylephrine and neomycin.
  • the neomycin and phenylephrine are always added after the temperature has been lowered since they are unstable to the heat required during emulsification.
  • the preferred emulsion form of the composition of the present invention is even more important in forming a satisfactory, physically stable suspension.
  • Phenylephrine tends to oxidize in the presence of amine oxidase, an enzyme found in the nasal mucosa.
  • the therapeutic effectiveness of phenylephrine is adversely affected by such oxidation.
  • One of the advantages of the composition of the present invention is its tendency to stabilize phenylephrine in the presence of amine oxidase.
  • the following table shows the effect of neomycin, hydrocortisone acetate, hydrocortisone alcohol, and the vehicle alone on the rate of oxidation of phenylephrine by amine oxidase.
  • the source of the enzyme used in the test was guinea pig liver. The rate of oxidation was measured manometrically. The reaction measured can be illustrated by the following formula:
  • the stability of the phenylephrine in the composition of the present invention is due to one of the ingredients in Tegacid Regular, the trade name for an emulsifying agent available from the Goldsehmidt Chemical Corp..- New York, N.Y., containing glyceryl monostearate and diethylaminoethyl oleyl amide phosphate.
  • the latter material is almost entirely responsible for this stability.
  • Diethylaminoethyl oleyl amide phosphate is prepared by re acting equivalent amounts of oleyl diethylaminoethyl amide and phosphoric acid in aqueous solution.
  • the diethylaminoethyl oleyl amide phosphate in Tegacid Regular consists mainly of oleyl-CONH-CH CH -NH (Et) 2 +H PO Tegacid Regular contains approximately five percent by weight of diethylaminoethyl oleyl amide phosphate, 7 the balance being almost entirely glyceryl monostearate.
  • composition of the present invention provides good to excellent results in the following conditions: nasal polyps, allergic rhinitis, acute sinusitis, chronic sinusitis, acute nasopharyngitis, chronic maxillary sinusitis, asthma due to sinus infection, basomotor rhinitis, hay fever, pollinosis, and the like.
  • Example 1 44,000 milliliters of the composition of the present invention is prepared from the following types and amounts of ingredients:
  • 25,000 milliliters of sterile water at a temperature of approximately ninety degrees centrigrade is transferred to a sterile, calibrated, stainless steel mixing tank fitted for rapid agitation. While agitating, a hot mixture of spermaceti, Tegacid, and polysorbate 80 is added aseptically. Rapid agitation is continued until the temperature of the emulsion is approximately 38 degrees centigrade.
  • Sterile aqueous solutions of myristyl gamma picolinium chloride, neomycin, phenylephrine, sodium chloride, sodium citrate and propylene glycol, and sterile micronized hydrocortisone acetate are added aseptically. This is mixed thoroughly for approximately two hours.
  • Sterile water is added to bring the composition up to volume and the whole is milled through a sterile colloid mill.
  • the composition is assayed for hydrocor-tisone acetate,, phenylephrine hydrochloride, neomycin, pH, particle size and sterility. Fifteen milliliters of the suspension-emulsion is filled into each sterile plastic squeeze bottle.
  • Example 2 Following the procedure of Example 1, a composition containing hydrocortisone free alcohol at a concentration of 0.5 percent is prepared by substituting 220 grams thereof for the hydrocortisone acetate in the formula given.
  • Example 3 Following the procedure of Example 1, a composition containing 11?,17 a-dihydroxy-21 acetoxy 1,4 pregnadiene-3,20-dione at a concentration of 0.1 percent is prepared by substituting 44 grams thereof for the hydrocortisone acetate in the formula given.
  • a concentration of 0.05 percent is prepared by substituting 22 grams.
  • Example 4 Following the procedure of Example 1, a composition containing 2 methyl 113,170 dihydroxy-Zl-acetoxy- 1,4-pregnadiene-3,20-dione at a concentration of 0.05 percent is prepared by substituting 22 grams thereof for the hydrocortisone acetate in the formula given.
  • Example 5 Following the procedure of Example 1, a composition containing 1704,21 dihydroxy 1,4 pregnadiene-3,11,20- trione at a concentration of 0.1 percent is prepared by substituting 44 grams thereof for the hydrocortisone acetate in the formula given.
  • Example 6 15,000 milliliters of the composition of the present invention is prepared from the following types and amounts of ingredients: Grams Deionized water, suflicient to make up 15,000 mls.
  • 12,000 milliliters of deionized water is heated in a suitable container to 70-75 degrees centigrade.
  • Sodium chloride, sodium citrate and myristyl gamma picolinium chloride and sorbic acid are dissolved therein.
  • Polysorbate 80 and propylene glycol are added.
  • the hydrocortisone acetate is dispersed thoroughly therein.
  • the glyceryl monostearate, diethylaminoethyl oleyl amide phosphate and spermaceti are added. While stirring thoroughly, the temperature is maintained at about 75 degrees centigrade for thirty minutes before cooling to room temperature.
  • the neomycin sulfate and phenylephrine are then dissolved therein.
  • Deionized water is added to make up a volume of 15,000 milliliters and the whole is stirred thoroughly.
  • compositions of this invention for many nasal conditions, a number of troublesome ear inflammations have also been treated with marked success.
  • antibacterial agents can also be added advantageously to any of the above compositions, such as one or more of polymyxin B sulfate about 2000 units per milliliter of emulsion, gramicidin about 0.005 percent, erythromycin about one percent, and a sulfonamide such as sodium sulfacetamide about five percent or 4-aminomethylbenzenesulfonarnide hydrochloride about five percent.
  • polymyxin B sulfate about 2000 units per milliliter of emulsion
  • gramicidin about 0.005 percent
  • erythromycin about one percent
  • a sulfonamide such as sodium sulfacetamide about five percent or 4-aminomethylbenzenesulfonarnide hydrochloride about five percent.
  • An antihistamine such as 1-(p-chlorophenyl)-1-(2- pyridyl)-'3-dimethylaminopropane gluconate about 0.25
  • a nasal spray composition comprising an anti-inflammatory adrenocor-ticosteroid, neomycin, and phenylephrine in a liquid vehicle suitable for nasal use.
  • a nasal spray composition comprising hydrocortisone, neomycin, and phenylephrine as the essential active ingredients and diethylaminoethyl oleyl amide phosphate as an emulsifier-stabilizer in an aerosol-type liquid vehicle.
  • a nasal spray composition comprising hy'drocortisone acetate, neomycin sulfate, l-phenylephrine hydrochloride, a preservative, and a humectant in an isotonic, aerosol-type oil-in-water emulsion.
  • a nasal spray composition comprising hydrocortisone acetate, neomycin sulfate, l-phenylephrine hydrochloride, spermaceti, propylene glycol, polysorbate 80, U.S.P., glyceryl monostearate, and diethylaminoethyl oleyl amide phosphate in an isotonic, aqueous, aerosoltype vehicle.
  • a nasal spray composition comprising from about 0.05 to 2.5 percent of an anti-inflammatory adrenocorticosteroid, about 0.6 percent neomycin, about 0.1 to one percent phenylephrine, and about 0.03 to 0.3 percent diethylaminoethyl oleyl amide phosphate in an isotonic, aerosol-type oil-in-water emulsion.
  • composition of claim 5 wherein the oil phase comprises glyceryl monostearate and spermaceti.
  • composition of claim 5 wherein the anti-inflammatory adrenocorticosteroid is hydrocortisone.
  • composition of claim 5 wherein the anti-inflammatory adrenocorticosteroid is hydrocortisone acetate.
  • composition of claim 5 wherein the anti-inflammatory adrenocorticosteroid is 11p,17a-dihydroxy-21- acetoxy-1,4-pregnadiene3,20-dione.
  • composition of claim 5 wherein the anti-inflammatory adrenocorticosteroid is 2'methyl-11fi,17a-dihydroxy-21-acetoxy-1,4-pregnadiene-3,ZO-dione.
  • composition of claim 5 wherein the anti-inflammatory adrenocortieosteroid is 17a,21-dihydroxy-1,4- pregnadiene-3,1 1,20-trione.

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Description

United States Patent""'O siguors to The Upjohn Company, I 1 u Micln, a
corporation of Michigan No Drawing. Filed June 8, 1955, Ser. No. 514,132 11 Claims. (Cl. 167-58) This invention relates to a therapeutic composition, more particularly a nasal preparation containing neomycin, an anti-inflammatory corticosteroid and phenylephrine.
The mucous membrane of the major portion of the nasal cavity is composed of the superficial ciliated columnar epithelium containing the terminal portion of the ducts from secretory mucous and serous glands, the basement membrane which is a band of collagen material of variable thickness underlying the ciliated epithelium, and the submucosa lying immediately under the basement membrane which is composed of connective tissue containing the mucous and serous glands, a network of blood vessels, nerves and lymphatics. This region is the predominant site of inflammatory reactions. 1
A thin mucous film normally covers the exposed ciliated epithelium. The cilia moving rhythmically cause the mucous film to flow backward to the pharynx to remove foreign matter including bacteria. The intact normally functioning nasal mucosa is on the whole quite resistant to infection. a
A number of factors may be implicated in the disruption of physiological integrity of the nasal mucosa. Sudden exposure to change in temperature and humidity, sensitivity to allergens (pollens, molds, bacteria), overexposure to irritants such as chemicals and smoke may contribute to changes in the mucosa and result in inflammation.
objectively, the picture is one of vascular congestion, edema, exudation and secretory dysfunction. These changes constitute a break in the integrity of the mucosa and predispose, to infection.
Swelling of the tissue which is most marked in the area of the tu'rbinates interferes with nasal breathing and drainage from the sinuses, and causes or perpetuates itching and sneezing. Extension of inflammation into the nasopharynx may obstruct the eustachian tube to cause the accumulation of fluid and create pressure disturbances in the middle ear.
Chronic inflammation produces several types of pathological changes in the nasal mucosa. Long standing edema or repeated allergic reactions favor polyp formation. 'It becomes evident that prompt suppression of inflammation will not only provide the patient with welcome relief but may also prevent complications.
-It is therefore an object of this invention to provide a therapeutic composition which iseffective in the treatment of nasal disorders. It is also an object of this invention to provide such a composition which provides a combination of active ingredients each of which enhances and supplements the activity of the other. A further object is the provision of such a preparation which reduces local edema in certain nasal conditions and thus improves the therapeutic action of the anti-inflammatory corticosteroid and/or neomycin. A still further object is the provision of such a composition which has greater antibiotic activity than neomycin alone. A further object is the provision of a combination which interferes less with cilial action than the individual components. Another object is the provision of such a composition which prolongs, increases, or otherwise improves the anti-inflammatory effect of the corticosteroid. A still further object is the provision of such a composition which improves the vasoconstrictor action of the phenylephrine by reducing its destruction by enzymes in the nasal mucosa. provision of such a composition which corrects vasomotor paralysis and restores the response of the mucosa,
to the vasoconstrictor. A still further object is the provision of such a composition which improves the spreadr ing and local tissue penetration of the anti-inflammatory. corticosteroid when applied topically. A still further object is the provision of such a composition which sup- A still which this invention pertains.
The foregoing and additional objects have been accom-.
plished by the provision of a therapeutic composition comprising neomycin, an anti-inflammatory corticosteroid and phenylephrine as the essential active ingredients, in a sprayable emulsion-type vehicle, preferably containing diethylaminoethyl oleyl amide phosphate.
Essentially the composition of the present invention is prepared by dispersing the active ingredients in a vehicle suitable for nasal use. It is preferred that the vehicle be a very thin, mobile, sprayable emulsion which holds the active ingredients particularly hydrocortisone, adequately suspended for long periods of time without loss in potency and without discoloration and in which even where some settling does occur after long periods of standing, resuspension is readily attained by slight shaking.
The difficulties involved in preparing an elfective, 'phys icall-y stable nasal preparation are considerable as witnessed by the following statement which appeared in the Journal of Allergy 25: 513 (1954):
Unfortunately, however, as certain attempts at our hospital and elsewhere have demonstrated, particulate suspensions of hydrocortisone acetate-at least in the concentrations heretofore used-cannot be uniformly dispersed on membrane surfaces, nor do they lend themselves well to aerosolization.
Furthermore, it has been a difiicult problem to prepare a stable emulsion of the viscosity required for spraying (preferably 1r1.3 centistokes, or 11.5 centipoises) which is capable of suspending relatively high concentrations of the insoluble hydrocortisones for long periods without agglomeration.
The phrase anti-inflammatory corticosteroid as used in the present specification means those adrenal cortical steroids and their derivatives which possess local anti-in flammatory activity, particularly on the mucous membranes. These corticosteroids include hydrocortisone (the preferred corticosteroid), cortisone, 9a-flu01O-1lfi, 17a dihydroxyprogesterone, 9oz fiuoro 11 keto-17ahydroxyprogesterone and the like.
The word hydrocortisone as used in the present specification means 17a-hydroxycorticosterone and its topically active derivatives, such as the 2l-esters including the acetate, the cyclopentylpropionate, and the like; the A analogs, such as 11B,l7u,21-trihydroxy-1,4-pregnadiene- 3,20-dione and its esters; the Z-methyl derivatives such as 2 methyl 1lfi,17a,2l tn'hydroxy 4 pregnene 3,20- dione and its esters; combinations of the foregoing derivatives, such as 2-methyl-11,9,17a,21-trihydroxy-1,4-pregna diene-3,20-dione and its esters; and the like. The 2- methyl derivatives and processes for their production are disclosed in copending application Serial Number 485,318, filed January 31, 1955, now Patent No. 2,923,720. 7
The word cortisone as used in the present specification means 17a-hydroxy-1l-dehydrocorticosterone and its topically active derivatives, such as the 2l-esters including Patented June 20, 1 1;
A still further object is the the acetate, the hemisuccinates, and the like; the A analogs, such as 17a,21-dihydroxy-1,4-pregnadiene-3,ll, 20-trione and its esters; and the like.
The word neomycin as used in the present specification means the antibiotic more fully described in Walesman, Neomycin, Rutgers University Press, 1953. it includes the various forms of neomycin (such as the B and C forms) and their therapeutically active derivatives (such as the sulfate and the hydrochloride salts).
The word phenylephrine as used in the present specification means 1 m hydroxy-ot-(methylaminomethyl)- benzyl alcohol and its therapeutically active salts (such as the hydrochloride salt). The compound is more particularly described in U.S. Patents 1,932,347 and 1,954,389.
In a preferred embodiment the composition of the present invention is prepared as a nasal spray in a buffered, isotonic base having a pH which is most advantageous for use on the nasal mucosa (a pH between about 5.5 and 6.5). The preparation must be nonirritating to the nasal mucosa. The vehicle for the active ingredients is preferably an oil-in-water emulsion. The emulsion is stabilized by an emulsifying or stabilizing agent, or combination of such agents, which prevents the oil globules from coalescing for long periods of time. The oil or fat phase in the preferred embodiment of the present invention comprises glyceryl monostearate and spermaeeti. The emulsifying agent in the preferred embodiment comprises polysorbate 80, U.S.P., and diethylaminoethyl oleyl amide phosphate. The diethylaminoethyl oleyl amide phosphate performs a dual function in that it also stabilizes the phenylephrine in the nasal mucosa by reducing enzyme oxidation thereof. This stabilization function applies both to the situation where phenylephrine is used alone as well as to one in which an anti-inflammatory corticosteroid and neomycin are also present in the composition. In order to. minimize irritation in the nose, the emulsion is preferably made isotonic using such materials as sodium chloride and/or sodium citrate. The latter also acts as a buffer to stabilize the pH. The emulsion is preferably preserved with myristyl gamma picolinium chloride and/or sorbic acid. A humectant, preferably propylene glycol, is also desirable; this material also aids in stabilizing the emulsion. In addition to the individual contributions of the separate ingredients, the combination of ingredients in the preferred embodiment of the present invention provides a composition possessing superior therapeutic and pharmaceutical properties.
The concentrations of the various active ingredients are important, particularly in the preferred embodiments of present invention. The amounts of the active ingredients used depend primarily upon the therapeutic activity of each ingredient. For example, the concentrations of the corticosteroid used would preferably vary from 0.05 percent for Z-methyl-l 1B,17a,21-trihydroxy-1,4-pregnadiene- 3,20-dione to 2.5 percent for hydrocortisone acetate. (All percentages are weight by volume unless otherwise specified.) An adequate concentration of neomycin is about 0.5 percent, although it is preferred to use an additional 0.1 percent to compensate for losses during manufacture and storage. There can be considerable variation of this amount without impairing the therapeutic effectiveness of the combination. Similarly, the concentration of phenylephrine preferably varies from 0.1 percent to one percent, especially 0.25 percent. The concentration of the fat or oil in the emulsion preferably ranges from two to four percent. Of the total composition 0.03 to 0.3 percent is preferably diethylaminoethyl oleyl amide phosphate. The desirable concentration of polysorbate 80 U.S.P. in the emulsion ranges from 0.25 to 1.5 percent, preferably 0.5 percent. Although considerable variation of these concentrations is possible, the best results are obtained within the preferred limits given.
In preparing the composition of the present invention, the micronized corticosteroid can be dispersed in the aqueous phase before the emulsification step. Where the 4 corticosteroid shows some decomposition at the emulsification temperature it is preferably dispersed in the emulsion after it is cooled either before, or at the same time as, the addition of the phenylephrine and neomycin. The neomycin and phenylephrine are always added after the temperature has been lowered since they are unstable to the heat required during emulsification. For aqucous dispersions of corticosteroids which are difiicult to wet, e.g., 113,170; dihydroxy 21 acetoxy 1,4 pregnadiene- 3,20-dione, the preferred emulsion form of the composition of the present invention is even more important in forming a satisfactory, physically stable suspension.
Phenylephrine tends to oxidize in the presence of amine oxidase, an enzyme found in the nasal mucosa. The therapeutic effectiveness of phenylephrine is adversely affected by such oxidation. One of the advantages of the composition of the present invention is its tendency to stabilize phenylephrine in the presence of amine oxidase. The following table shows the effect of neomycin, hydrocortisone acetate, hydrocortisone alcohol, and the vehicle alone on the rate of oxidation of phenylephrine by amine oxidase. The source of the enzyme used in the test was guinea pig liver. The rate of oxidation was measured manometrically. The reaction measured can be illustrated by the following formula:
The data show that additions of neomycin, hydrocortisone alcohol or acetate, alone or in combination had little or no inhibitory effect on the oxidation of phenylephrine by amine oxidase. The vehicle inhibited the oxidation of phenylephrine by 21 and 27 percent in different experiments. The rate of oxidation of the phenylephrine was still lower when the whole composition was tested than when the various ingredients were added separately. The reason for this is unknown.
The stability of the phenylephrine in the composition of the present invention is due to one of the ingredients in Tegacid Regular, the trade name for an emulsifying agent available from the Goldsehmidt Chemical Corp..- New York, N.Y., containing glyceryl monostearate and diethylaminoethyl oleyl amide phosphate. The latter material is almost entirely responsible for this stability. Diethylaminoethyl oleyl amide phosphate is prepared by re acting equivalent amounts of oleyl diethylaminoethyl amide and phosphoric acid in aqueous solution. The diethylaminoethyl oleyl amide phosphate in Tegacid Regular consists mainly of oleyl-CONH-CH CH -NH (Et) 2 +H PO Tegacid Regular contains approximately five percent by weight of diethylaminoethyl oleyl amide phosphate, 7 the balance being almost entirely glyceryl monostearate.
Clinical trial in humans has shown that the composition of the present invention provides good to excellent results in the following conditions: nasal polyps, allergic rhinitis, acute sinusitis, chronic sinusitis, acute nasopharyngitis, chronic maxillary sinusitis, asthma due to sinus infection, basomotor rhinitis, hay fever, pollinosis, and the like.
- The following examples are illustrative of the processes and compositions of this invention and are not to be construed as limiting.
Example 1 44,000 milliliters of the composition of the present invention is prepared from the following types and amounts of ingredients:
Water for injection, sufiicient to make up 44,000 mls.
25,000 milliliters of sterile water at a temperature of approximately ninety degrees centrigrade is transferred to a sterile, calibrated, stainless steel mixing tank fitted for rapid agitation. While agitating, a hot mixture of spermaceti, Tegacid, and polysorbate 80 is added aseptically. Rapid agitation is continued until the temperature of the emulsion is approximately 38 degrees centigrade. Sterile aqueous solutions of myristyl gamma picolinium chloride, neomycin, phenylephrine, sodium chloride, sodium citrate and propylene glycol, and sterile micronized hydrocortisone acetate are added aseptically. This is mixed thoroughly for approximately two hours. Sterile water is added to bring the composition up to volume and the whole is milled through a sterile colloid mill. The composition is assayed for hydrocor-tisone acetate,, phenylephrine hydrochloride, neomycin, pH, particle size and sterility. Fifteen milliliters of the suspension-emulsion is filled into each sterile plastic squeeze bottle.
Example 2 Following the procedure of Example 1, a composition containing hydrocortisone free alcohol at a concentration of 0.5 percent is prepared by substituting 220 grams thereof for the hydrocortisone acetate in the formula given.
Example 3 Following the procedure of Example 1, a composition containing 11?,17 a-dihydroxy-21 acetoxy 1,4 pregnadiene-3,20-dione at a concentration of 0.1 percent is prepared by substituting 44 grams thereof for the hydrocortisone acetate in the formula given.
A concentration of 0.05 percent is prepared by substituting 22 grams.
Example 4 Following the procedure of Example 1, a composition containing 2 methyl 113,170 dihydroxy-Zl-acetoxy- 1,4-pregnadiene-3,20-dione at a concentration of 0.05 percent is prepared by substituting 22 grams thereof for the hydrocortisone acetate in the formula given.
Example 5 Following the procedure of Example 1, a composition containing 1704,21 dihydroxy 1,4 pregnadiene-3,11,20- trione at a concentration of 0.1 percent is prepared by substituting 44 grams thereof for the hydrocortisone acetate in the formula given.
Example 6 15,000 milliliters of the composition of the present invention is prepared from the following types and amounts of ingredients: Grams Deionized water, suflicient to make up 15,000 mls.
12,000 milliliters of deionized water is heated in a suitable container to 70-75 degrees centigrade. Sodium chloride, sodium citrate and myristyl gamma picolinium chloride and sorbic acid are dissolved therein. Polysorbate 80 and propylene glycol are added. The hydrocortisone acetate is dispersed thoroughly therein. The glyceryl monostearate, diethylaminoethyl oleyl amide phosphate and spermaceti are added. While stirring thoroughly, the temperature is maintained at about 75 degrees centigrade for thirty minutes before cooling to room temperature. The neomycin sulfate and phenylephrine are then dissolved therein. Deionized water is added to make up a volume of 15,000 milliliters and the whole is stirred thoroughly.
In addition to the unexpected advantages shown by the compositions of this invention for many nasal conditions, a number of troublesome ear inflammations have also been treated with marked success.
Other antibacterial agents can also be added advantageously to any of the above compositions, such as one or more of polymyxin B sulfate about 2000 units per milliliter of emulsion, gramicidin about 0.005 percent, erythromycin about one percent, and a sulfonamide such as sodium sulfacetamide about five percent or 4-aminomethylbenzenesulfonarnide hydrochloride about five percent.
An antihistamine, such as 1-(p-chlorophenyl)-1-(2- pyridyl)-'3-dimethylaminopropane gluconate about 0.25
percent and 2-[(2-dimethylaminoethyl) (p-methoxybenzyl)amino] pyrimidine hydrochloride about 0.3 percent, can also be added to any of the formulations of this invention.
It is to be understood that the invention is not to be limited to the exact details of operation or exact compositions shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.
We claim:
1. A nasal spray composition comprising an anti-inflammatory adrenocor-ticosteroid, neomycin, and phenylephrine in a liquid vehicle suitable for nasal use.
2. A nasal spray composition comprising hydrocortisone, neomycin, and phenylephrine as the essential active ingredients and diethylaminoethyl oleyl amide phosphate as an emulsifier-stabilizer in an aerosol-type liquid vehicle.
3. A nasal spray composition comprising hy'drocortisone acetate, neomycin sulfate, l-phenylephrine hydrochloride, a preservative, and a humectant in an isotonic, aerosol-type oil-in-water emulsion.
4. A nasal spray composition comprising hydrocortisone acetate, neomycin sulfate, l-phenylephrine hydrochloride, spermaceti, propylene glycol, polysorbate 80, U.S.P., glyceryl monostearate, and diethylaminoethyl oleyl amide phosphate in an isotonic, aqueous, aerosoltype vehicle.
5. A nasal spray composition comprising from about 0.05 to 2.5 percent of an anti-inflammatory adrenocorticosteroid, about 0.6 percent neomycin, about 0.1 to one percent phenylephrine, and about 0.03 to 0.3 percent diethylaminoethyl oleyl amide phosphate in an isotonic, aerosol-type oil-in-water emulsion.
6. The composition of claim 5 wherein the oil phase comprises glyceryl monostearate and spermaceti.
7. The composition of claim 5 wherein the anti-inflammatory adrenocorticosteroid is hydrocortisone.
8. The composition of claim 5 wherein the anti-inflammatory adrenocorticosteroid is hydrocortisone acetate.
9. The composition of claim 5 wherein the anti-inflammatory adrenocorticosteroid is 11p,17a-dihydroxy-21- acetoxy-1,4-pregnadiene3,20-dione.
10. The composition of claim 5 wherein the anti-inflammatory adrenocorticosteroid is 2'methyl-11fi,17a-dihydroxy-21-acetoxy-1,4-pregnadiene-3,ZO-dione.
lLThe composition of claim 5 whereinthe anti-inflammatory adrenocortieosteroid is 17a,21-dihydroxy-1,4- pregnadiene-3,1 1,20-trione.
References Cited in the file of this patent UNITED STATES PATENTS 2,684,946 Schmitz July 27, 1954 2,730,483 Mast Jan. 10, 1956 2,786,835 Pinson Mar. 26, 1957 2,801,202 Poetsch July 30, 1957 OTHER REFERENCES 0 gents, vol. II, 1958, p. 227 footnotes.

Claims (1)

1. A NASAL SPRAY COMPOSITION COMPRISING AN ANTI-INFLAMMATORY ADRENOCORTICOSTEROID, NEOMYCIN, AND PHENYLEPHRINE IN A LIQUID VEHICLE SUITABLE FOR NASAL USE.
US514132A 1955-06-08 1955-06-08 Anti-inflammatory and anti-bacterial decongestant nasal spray compositions Expired - Lifetime US2989437A (en)

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US3076745A (en) * 1958-11-17 1963-02-05 Poultry Service And Res Corp Antibiotic method for promoting poultry growth
US3079299A (en) * 1959-11-16 1963-02-26 Gen Aerosol Corp Self-propelling medicinal ointment composition containing polyethylene and method ofapplication
EP0053754A1 (en) * 1980-12-06 1982-06-16 Reichert, Dietrich, Dr. med. Drug for antagonizing snore, and method for its application
EP0246652A3 (en) * 1986-05-22 1988-02-03 Syntex (U.S.A.) Inc. Aqueous steroid formulations for nasal administration
US20040185093A1 (en) * 2003-03-18 2004-09-23 Szymczak Christopher E. Compositions containing sucralose
US20040208830A1 (en) * 2003-04-16 2004-10-21 Imtiaz Chaudry Nasal pharmaceutical formulations and methods of using the same
US20040209852A1 (en) * 2003-04-16 2004-10-21 Imtiaz Chaudry Formulations and methods for treating rhinosinusitis
US20040235807A1 (en) * 2003-05-21 2004-11-25 Weinrich Karl P. Formulations including a topical decongestant and a topical corticosteroid suitable for nasal administration and method for treating obstructive sleep apnea
US20060062811A1 (en) * 2004-09-21 2006-03-23 Szymczak Christopher E Medicinal cooling emulsions
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2684946A (en) * 1948-10-01 1954-07-27 Goldschmidt Ag Th Washing and disinfecting composition
US2730483A (en) * 1952-08-12 1956-01-10 Nepera Chemical Co Inc Therapeutic compositions comprising neomycin, gramicidin and quaternary ammonium salt of thonzylamine
US2786835A (en) * 1954-08-24 1957-03-26 Pfizer & Co C Hydrocortisone pharmaceutical compositions
US2801202A (en) * 1954-12-24 1957-07-30 Smith Kline French Lab Compositions containing cortisone or hydrocortisone with phenylephrine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2684946A (en) * 1948-10-01 1954-07-27 Goldschmidt Ag Th Washing and disinfecting composition
US2730483A (en) * 1952-08-12 1956-01-10 Nepera Chemical Co Inc Therapeutic compositions comprising neomycin, gramicidin and quaternary ammonium salt of thonzylamine
US2786835A (en) * 1954-08-24 1957-03-26 Pfizer & Co C Hydrocortisone pharmaceutical compositions
US2801202A (en) * 1954-12-24 1957-07-30 Smith Kline French Lab Compositions containing cortisone or hydrocortisone with phenylephrine

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US4556557A (en) * 1980-12-06 1985-12-03 Dietrich Reichert Method and composition for combating snoring, and the use of surface active substances for the preparation of said composition
US4668513A (en) * 1980-12-06 1987-05-26 Dietrich Reichert Method for combating snoring
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