(12) United States Patent
`Haslwanter et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,316,483 B1
`*Nov. 13,2001
`
`US006316483B1
`
`OXYMETAZOLINE HCI AND/OR
`CHLORI-‘HEN IRAMIN E MALEATE NASAL
`SPRAY COMPOSITIONS
`
`Inventors: Joseph A. Haslwanter, Germantown;
`William F. Rencher, Cordova, both of
`TN (US)
`
`Assignee: Schering Corporation, Kenilworth, NJ
`(US)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`C07D/471/14
`
`0 571 671—A1 * 12/1993 (EP) .
`0 498 290 A1
`8/1992 (EP)
`3287535
`12/1991 (JP).
`A61K/31/435
`62—123116
`6/1987 (.IP)
`.... .. A61K/31/57
`1—168619
`7/1989 (JP)
`4—99731
`3/1992 (JP) ............................. .. A61K/47/30
`WO
`94/05330—A1 *
`WO 94/11100
`8404346
`
`3/1994 (wo).
`5/1994 (wo) ............. ..
`12/1984 (ZA).
`
`..... .. B01J/13/02
`
`OTHER PUBLICATIONS
`
`Martindale The Extra Pharmacopoeia (1989) p. 841.*
`
`This patent is subject to a terminal dis-
`claimer.
`
`Remington’s Pharmaceutical Sciences (1985), pp. 889,
`1127, 1159, 1299, 1305, 1309 & 1500.*
`
`Appl. No.: 09/434,075
`
`Filed:
`
`Nov. 5, 1999
`
`Related U.S. Application Data
`
`Continuation of application No. 09/163,638, filed on Sep.
`30, 1998, now abandoned, which is a continuation of appli-
`cation No. 08/964,038, filed on Nov. 4, 1997, now Pat. No.
`5,897,858, which is a continuation of application No.
`08/375,014, filed on Jan. 19, 1995, now abandoned, which
`is a continuation—in—part of application No. 08/191,402, filed
`on Feb. 3, 1994, now abandoned.
`
`I11t. Cl.7 ........................ .. A61K 31/415; A61K 9/72,
`A01N 43/50
`.... .. 514/401; 514/853
`424/434; 514/401,
`514/853
`
`Field of Search ....... ..
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`.... ..
`
`.............. .. 167/65
`............ .. 424/177
`
`11/1958 Dale et al.
`2,861,920
`11/1982 Sieber et al.
`4,358,439
`9/1984 Wolf et al. .
`4,470,965
`4/1986 Su et al. .
`4,581,225
`. 424/81
`3/1988 Shimizu et al.
`4,728,509
`.. 424/448
`4/1989 Sanderson
`4,818,541
`514/282
`11/1989 Frost
`..... ..
`4,880,813
`514/18
`3/1990 Giertz et al.
`4,906,614
`4,910,225
`.................. .. 514/561
`3/1990 Ogawa et al.
`4,952,402
`............ .. 424/419
`8/1990 Sparks et al.
`3/1991 Chibret ............................ 424/43
`5,000,936
`5,114,979
`5/1992 Kielley .
`5/1992 Gilbert et al.
`5,116,847
`11/1992 Hettche
`5,164,194
`11/1992 Sims et al.
`5,164,398
`1/1993 Arai et al.
`5,177,223
`11/1993 Weber et al.
`5,262,568
`10/1994 Yamamoto et al.
`5,356,620
`5,366,972
`11/1994 Hargrave et al.
`5/1995 lkejiri et al.
`.
`5,419,898
`...................... .. 514/632
`11/1998 Goldin et al.
`5,837,737
`4/1999 Haslwanter et al.
`.............. 424/78.04
`5,897,858 *
`FOREIGN PATENT DOCUMENTS
`
`.
`
`.
`
`................ .. 424/489
`514/282
`.. 548/500
`564/238
`424/78.04
`.................. .. 514/220
`
`.
`
`0109 561—A1
`0454 617—A1
`0 380 367—B1
`
`5/1984 (EP).
`4
`* 10/1991
`(EP).
`* 12/1993 (EP).
`
`Kublik, H. et al., “Rheological Properties of Polymer Solu-
`tions as Carriers for Nasal Drug Delivery Systems,” Eur. J.
`Pharm. Biopharm, 39 (5) pp. 192-196 (1993).*
`
`Rozier, A. et al., “Gelrite: A Novel, Ion-Activated, In-Situ
`Gelling Polymer for Opthalmic Vehicles,” International
`Journal of Pharmaceutics, 57, pp. 163-168 (1989).*
`
`Physicians’ Desk Reference for Nonprescription Drugs pp.
`754-755 (Medical Economics Company 1998).*
`
`“Auxiliary Substances in Technology of Drug Form,”
`Rybacki and T. Stozek, Warsaw (1980), Vol. 7, Sections
`Titled, “Polyoxyethylene Glycols” and “PolyVir1ylpyrroli-
`done” (English Translation).
`
`Physician ‘s Desk Reference for Non Prescription Drugs,
`(1993), pp. 699-700.
`
`U.S.P. XXII, pp. 1118 and 1763.
`
`Pharmaceutical Dosage Forms, V0l. 2, edited by Herbert A.
`Iieberman, et al., Marcel Dekker Inc., New York, USA,
`(1989), pp. 180-187, 199.
`
`lecna/ogica Farnzaceutica, Dr. Edmundo Montalvo, pp. 73,
`74 and 75.
`
`Cl1e111.Abs.: Vol. 116, No. 18, No. 181179, May 7, 1992,
`JP-A-040266 17. *
`
`Chem. Abs.: Vol. 108, No. 24, No. 210213, Jun. 13, 1988,
`JP-A-62223131.*
`
`* cited by examiner
`
`Primary Examiner—Thurman K. Page
`Assistant Examiner-P. E. McQueeney
`(74) Attorney, Agent, or Firm—Arthur Mann; William Lee
`
`(57)
`
`ABSTRACT
`
`Aqueous nasal spray compositions comprising a medica-
`ment and an aqueous carrier comprising water soluble
`polymers selected from the group consisting of polyvi-
`nylpyrrolidonc and mixtures thereof.
`
`15 Claims, N0 Drawings
`
`APOTEX EX1061
`
`Page 1
`
`

`
`US 6,316,483 B1
`
`1
`OXYMETAZOLINE HCI AND/OR
`CHLORPHENIRAMINE MALEATE NASAL
`SPRAY COMPOSITIONS
`
`This is a continuation of application Ser. No. 09/163,638,
`filed Sep. 30, 1998, now abandoned which is a continuation
`of application Ser. No. 08/964,038, filed Nov. 4, 1997, which
`issued as U.S. Pat. No. 5,897,858; which was a continuation
`of application Ser. No. 08/375,014, filed Jan. 19, 1995, now
`abandoned; which was a continuation-in-part of application
`Ser. No. 08/191,402, filed Feb. 3, 1994, now abandoned.
`
`BACKGROUND OF THE INVENTION
`
`This invention relates to aqueous nasal compositions
`comprising a medicament in an aqueous carrier containing a
`water soluble polymer selected from the group of polyvi-
`nylpyrrolidone and mixtures thereof. The combination of
`water soluble polymers provides unexpected properties
`which enhance medicinal efficacy and promotes organolep-
`tic acceptance of the compositions
`One of the major hindrances to effective systemic absorp-
`tion of medicaments such as chlorpheniramine maleate in
`the nose is due to anatomical features of the epithelium
`within the nasal cavity. The constant beating of the nasal
`cilia causes the mucus film to continually move toward the
`nasopharynx. This action, in about 8 to 10 minutes, will
`remove the medicament from the nasal mucosa reducing the
`time for effective systemic absorption.
`Certain medicaments are active topically and are not
`systemically absorbed, such as the topically active nasal
`decongestant oxymetazoline hydrochloride. This medica-
`ment is a vasoconstrictor that increases nasal airway volume
`by reducing blood flow to the nasal capillary bed. Oxymeta-
`zoline hydrochloride also reduces blood flow to the muco-
`secreting cells and as a result reduces nasal secretions. This
`reduction of natural moisture replacement in conjunction
`with moisture vaporization due to increased air flow volume
`promotes drying of the nasal cavity. Loss of this protective
`mucosal film may result in an increased occurrence in nasal
`sensitivity and associated burning and stinging.
`It is known that when a combination of medicaments,
`such as chlorpheniramine maleate and oxymetazoline
`hydrochloride are incorporated into typical nasal spray for-
`mulations the occurrence of nasal burning and stinging
`increases.
`
`Nasal drying and the associated stinging within the nasal
`cavity is one of the most common complaints of patients and
`consumers that use nasal spray products. Other common
`nasal product negative attributes include odor, taste and the
`tendency of the product to run out of the nose.
`We have surprisingly discovered that incorporation of a
`combination of water soluble polymers selected from the
`group consisting of polyvinylpyrrolidone, polyethylene gly-
`col and mixtures thereof into nasal spray compositions
`provide enhanced medicinal efficacy and promotes organo-
`leptic acceptance of the compositions.
`It is an object of the present invention to provide nasal
`spray compositions exhibiting increased nasal retention of
`medicaments in the nasal cavity for enhanced topical or
`systemic activity.
`Another object of the present invention is to provide nasal
`spray compositions exhibiting reduced post nasal drip.
`It is a further object of the present invention to provide
`nasal spray compositions exhibiting increased moisturiza-
`tion in the nasal cavity.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`A further object of the present invention is to provide
`nasal spray compositions which reduce the potential of
`medicament induced stinging, burning, overdrying or irri-
`tation.
`
`SUMMARY OF INVENTION
`
`The present invention provides aqueous nasal spray com-
`positions comprising a medicament and an aqueous carrier
`containing a water soluble polymer selected from the group
`consisting of polyvinylpyrrolidone and mixtures thereof.
`The present invention provides aqueous nasal spray com-
`positions comprising an effective amount of a medicament
`in an aqueous carrier comprising:
`0 0.50 to 15.00% by weight/volume of a water soluble
`polymer selected from the group consisting of polyvi-
`nylpyrrolidone and mixtures thereof;
`0.00 to 15 .00% by weight/volume of polyethylene glycol;
`0.00 to 10.00% by weight/volume of a moisturizing agent
`or mixtures of moisturizing agents;
`0.00 to 10.00% by weight/volume of an antioxidant;
`0.001 to 0.10% by weight/volume of an antimicrobial
`preservative;
`0.00 to 5.00% by weight/volume of an aromatic alcohol;
`a sufficient amount of a pharmaceutically acceptable
`buffer to maintain the pH of the composition within the
`range of about 4.0 to 8.0 and
`QS water.
`The present invention further provides a method of treat-
`ing nasal conditions by administering to a nasal passage of
`a patient an aqueous nasal spray composition of the present
`invention.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The aqueous nasal spray compositions of the present
`invention comprise a medicament in an aqueous carrier
`containing a water soluble polymer selected from the group
`consisting of polyvinylpyrrolidone and mixtures thereof.
`Compositions of the present invention contain a thera-
`peutically effective amount of at least one pharmaceutically
`acceptable medicament. The medicament drug may be
`selected from a wide range of therapeutic agents and mix-
`tures of therapeutic agents. Illustrative categories and spe-
`cific examples include. analgesics, such as ibuprofen and
`ketoprofen; antiasmatics, such as theophylline; antitussives,
`such as noscapine and chlophedinol hydrochloride;
`antihistamines, such as chlorpheniramine maleate,
`loratadine, azatadine; antinauseant, such as dimenhydrinate;
`decongestants, such as oxymetazoline hydrochloride; vari-
`ous alkaloids, such as codeine sulfate and morphine;
`stimulants, such as nicotine; mucolytics, such as acetylcys-
`teine and bromhexine.
`
`The preferred medicaments, alone or in combination,
`include chlorpheniramine maleate and oxymetazoline
`hydrochloride.
`The amount of oxymetazoline hydrochloride found suf-
`ficient to effect nasal decongestion is from about 0.001 to
`about 0.2% by wt/vol of the total composition. Ranges of
`0.01 to 0.1% of the total composition are particularly
`suitable. Typically, 0.05% by wt/vol is preferred for adults
`and children above five years of age.
`The amount of chlorpheniramine maleate found sufficient
`for intranasal antihistamine action is from about 0.001 to
`
`about 2.0% by wt/vol of the total composition. Ranges of 0.1
`to 0.5% by wt/vol is most preferable.
`
`Page 2
`
`Page 2
`
`

`
`US 6,316,483 B1
`
`3
`Various gums and polymers have been evaluated to deter-
`mine suitability of such materials as bioadhesives to extend
`the nasal muco-cilia clearance time of nasal spray formula-
`tions. Desired properties of a bioadhesive include solubility
`clarity and compatibility in a conventional nasal spray
`formulation. In addition, the nasal spray composition con-
`taining the bioadhesive material was evaluated to determine
`the concentration effect on spray pattern and resultant mist
`properties.
`It has been found that polyvinylpyrrolidone, a linear
`polymer 1-vinyl-2-pyrrolidone, hereinafter designated PVP,
`extends muco-cilia clearance times of nasal spray compo-
`sition Polyvinylpyrrolidone, also known as Povidone,
`is
`commercially available as a series of products having mean
`molecular weights ranging from about 10,000 to about
`700,000. The various products are marketed according to
`average molecular weights designated K-values; e.g. GAF
`Corporation supplies PVP having the following K-values:
`
`K-value
`
`Average Molecular Weight
`
`15
`30
`60
`90
`
`about 10,000
`about 40,000
`about 160,000
`about 360,000
`
`The nasal spray compositions of this invention contain
`various grades of polyvinylpyrrolidone,
`i.e. K-15, K-30,
`K-60 and K-90. The polyvinylpyrrolidone ingredient may be
`present as one specific grade or as a combination of two or
`more grades.
`The most preferable polymers of polyvinylpyrrolidone for
`the compositions of this invention are PVP K-30 and PVP
`K-90.
`
`The amount of polyvinylpyrrolidone present in the com-
`positions of this invention is from about 0.50 to 15.00% by
`weight/volume of the total composition. Ranges of 0.50 to
`2.5% by weight/volume of the total composition are par-
`ticularly suitable and a range of 1.00 to 1.50% by weight/
`volume of the total composition being most preferable.
`To evaluate the effect of polyvinylpyrrolidone on nasal
`muco-cilia clearance time, a modified procedure was
`employed as disclosed by E. Puchelle, et al.,
`in Acta
`Otolarynogol, 91, 297-303. (1981). The procedure utilized
`a concentrated sodium saccharin solution as the indicator. A
`
`100 mcl dose of water-soluble polymer test solution was
`sprayed into the nose. After spraying, a cotton swab satu-
`rated with saccharin solution was inserted into the nostril
`
`and wiped around the ostuim depositing the saccharin onto
`the nasal mucosal lining. The clearance time was defined as
`the time for deposit of saccharin in the ostuim to the time the
`saccharin was tasted in the back of the throat/mough.
`Experimental results of this testing indicated that polyvi-
`nylpyrrolidone would extend nasal muco-cilia clearance
`times. For example, it was found that incorporation of PVP
`K-90 at 0.25% would extend nasal muco-cilia clearance
`times from the normal 8 to 10 minutes to 20 to 25 minutes.
`
`The use of water soluble polyethylene glycol (PEG)
`polymers in the compositions of this invention promotes
`moisturization of the nasal spray compositions in- the nasal
`cavity. Polyethylene glycol is a linear polymer formed by the
`addition reaction of ethylene glycol with ethylene oxide and
`are commercially available in average molecular weights
`ranging from about 200 to greater than 20,000. The com-
`mercially available grades of polyethylene glycol are mar-
`
`4
`keted based on the average molecular weight, i.e. the grade
`nomenclature is identified with the molecular weight. For
`example, PEG 400 represents material with an average
`molecular weight of 400 and the material with an average
`molecular of 600 is known as PEG 600. PEG 200, 300, 400,
`and 600 are clear viscous liquids at room temperature; PEG
`900, 1000, 1450, 3350, 4500 and 8000 are white, waxy
`solids.
`
`The preferred polyethylene glycols for the compositions
`of this invention are PEG 400 to PEG 3350;
`the most
`preferred polyethylene glycol is PEG 1450.
`The amount of polyethylene glycol present in the com-
`positions of this invention is from about 0.00 to 15.0% by
`weight/volume of the total composition. Ranges of 0.5% to
`10% by weight/volume of the total composition are particu-
`larly suitable and a range of 2.5 to 5% by weight/volume is
`most preferable.
`The compositions of the present invention may contain an
`aromatic alcohol selected from the group consisting of
`benzyl alcohol and phenyl ethyl alcohol. The amount of
`aromatic alcohol present in the composition is from about 0
`to 5.00% by weight/volume of the total composition. Ranges
`of 0.20—3.00% by weight/volume of the total composition
`are particularly suitable, and a range of 0.25 to 1.00% by
`weight/volume of the total composition being most prefer-
`able.
`
`The compositions of the present invention may contain
`moisturizing agent. Examples of moisturizing agents useful
`in the compositions of this invention include propylene
`glycol, glycerin and the like. Mixtures of such moisturizing
`agents are also useful in the compositions. The amount of
`moisturizing agent presents in the composition is from about
`0 to 10% by weight/volume of the total composition. Ranges
`of 1.00 to 4.00% by weight/volume of the total composition
`are particularly suitable, and a range of 1.5 to 3.50% by
`weight/volume of the total composition being most prefer-
`able.
`
`The compositions of the present invention may contain a
`pharmaceutically acceptable antioxidant, e.g. disodium
`EDTA. The amount of antioxident present in the composi-
`tion is from about 0 to 0.10% by weight/volume of the total
`composition. Ranges of 0.01 to 0.05% by weight/volume of
`the total composition are particularly suitable, and a range of
`0.015 to 0.030% by weight/volume of the total composition
`being most preferable.
`The compositions of the present invention contains at
`least one antimicrobial preservative in the range of 0.001%
`to about 0.3% by weight/volume of the composition. A
`typical suitable preservative which functions as an antimi-
`crobial agent
`includes the commercially available
`preservative, benzalkonium chloride in the range of about
`0.02 to about 0.025% by weight/volume.
`The compositions of the present invention also include
`pharmaceutically acceptable buffers sufficient to adjust and
`maintain the pH of the compositions of the present invention
`in the range of about 4.0 to about 8.0, preferably about 5.5
`to about 7.0 and 6.25 to 6.75 being most preferable. Typi-
`cally suitable buffers include citrate, phosphate and glycine.
`The nasal spray compositions of the present invention is
`manufactured in a conventional manner by thoroughly mix-
`ing the ingredients at ambient or elevated temperatures in
`order to achieve solubility of ingredients where appropriate.
`All percentages are by weight/volume. The definitions of
`components whose chemical composition is not immedi-
`ately clear from the name used may be found in the CTFA
`Cosmetic Ingredients Dictionary, 4th Edition, 1991, pub-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Page 3
`
`Page 3
`
`

`
`US 6,316,483 B1
`
`5
`lished by Cosmetic Toiletry and Fragrance Association, Inc.,
`Washington, DC.
`
`The following examples describe in detail the invention.
`It will be apparent to those skilled in the art that modifica-
`tions may be practiced without departing from the purpose
`and intent of this disclosure.
`
`EXAMPLE 1
`
`An aqueous nasal spray composition is prepared from the
`following:
`
`INGREDIENTS
`
`% Wt/Vol
`
`Water
`Disodium EDTA
`Sodium Phosphate Dibasic
`Sodium Phosphate Monobasic
`PVP K-90
`PVP K-30
`PEG 1450
`Benzyl Alcohol
`Benzalkonium Chloride (17% solution)
`Chlorpheniramine Maleate
`Oxymetazoline Hydrochloride
`
`QS
`0.0200
`0.0975
`0.5525
`0.2500
`1.0000
`2.5000
`0.2500
`0.0200
`0.5000
`0.0500
`
`The solution is prepared according to the following pro-
`cedure.
`
`To any appropriate reaction container, add 70% of the
`water and heat to 50° C. Add the following: sodium phos-
`phate monobasic, sodium phosphate dibasic, disodium
`EDTA and benzyl alcohol to the water. Mix each ingredient
`addition for at least 5 minutes. With continued mixing add
`the water soluble polymers, i.e.
`the polyvinylpyrrolidone
`(PVP) and the polyethylene glycol (PEG). Mix each ingre-
`dient addition for at least 5 minutes. With continued mixing
`add the oxymetazoline hydrochloride and chlorpheniramine
`maleate; mix each ingredient addition for at least 5 minutes.
`While mixing, add the benzalkonium chloride 17% solution
`and mix for at least 5 minutes. With continued mixing, the
`solution is cooled to 30° C. Adjust the final batch Volume
`with water, mix until uniform and then filter using conven-
`tional filtration equipment.
`
`EXAMPLE 2
`
`6
`EXAMPLE 3
`
`An aqueous nasal spray composition is prepared from the
`following:
`
`INGREDIENTS
`
`Water
`Disodium EDTA
`Sodium Phosphate Dibasic
`Sodium Phosphate Monobasic
`PVP K-30
`PEG 600
`Benzyl Alcohol
`Benzalkonium Chloride (17% solution)
`Oxymetazoline Hydrochloride
`Chlorpheniramine Maleate
`
`% Wt/Vol
`
`QS
`0.0200
`0.0975
`0.5525
`3.0000
`5.0000
`0.2500
`0.0200
`0.0500
`0.5000
`
`The composition is prepared according to the procedure in
`Example 1.
`
`EXAMPLE 4
`
`An aqueous nasal spray composition is prepared from the
`following:
`
`INGREDIENTS
`
`Water
`Disodium EDTA
`Sodium Phosphate Dibasic
`Sodium Phosphate Monobasic
`PVP K-30
`PEG 1450
`Benzyl Alcohol
`Benzalkonium Chloride (17% solution)
`Oxymetazoline Hydrochloride
`Chlorpheniramine Maleate
`
`% Wt/Vol
`
`QS
`0.0200
`0.0975
`0.5525
`3.0000
`5.0000
`0.2500
`0.0200
`0.0500
`0.5000
`
`The composition is prepared according to the procedure in
`Example 1.
`
`EXAMPLE 5
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`An aqueous nasal spray composition is prepared from the
`following:
`
`50
`
`An aqueous nasal spray composition is prepared from the
`following:
`
`INGREDIENTS
`
`Water
`Disodium EDTA
`Sodium Phosphate Dibasic
`Sodium Phosphate Monobasic
`PVP K-90
`PVP K-30
`PEG 1450
`Benzyl Alcohol
`Benzalkonium Chloride (17% solution)
`Oxymetazoline Hydrochloride
`
`% Wt/Vol
`
`QS
`0.0200
`0.0975
`0.5525
`0.2500
`1.0000
`2.5000
`0.2500
`0.0200
`0.0500
`
`55
`
`60
`
`65
`
`INGREDIENTS
`
`Water
`Disodium EDTA
`Sodium Phosphate Dibasic
`Sodium Phosphate Monobasic
`PVP K-90
`PVP K-30
`PEG 1450
`Propylene glycol
`Benzalkonium Chloride (17% solution)
`Oxymetazoline Hydrochloride
`
`% Wt/Vol
`
`QS
`0.0200
`0.0975
`0.5525
`0.1000
`3.0000
`2.5000
`0.2500
`0.1471
`0.0500
`
`The composition is prepared according to the procedure in
`Example 1.
`
`The composition is prepared according to the procedure in
`Example 1.
`
`Page 4
`
`Page 4
`
`

`
`US 6,316,483 B1
`
`7
`EXAMPLE 6
`
`An aqueous nasal spray composition is prepared from the
`following:
`
`INGREDIENTS
`
`% Wt/Vol
`
`Water
`Disodium EDTA
`Sodium Phosphate Dibasic
`Sodium Phosphate Monobasic
`PVP K-90
`PVP K-30
`PEG 1450
`Propylene Glycol
`Glycerin
`Benzalkonium Chloride (17% solution)
`Oxymetazoline Hydrochloride
`
`QS
`0.0200
`0.0975
`0.5525
`0.1000
`3.0000
`5.0000
`2.0000
`0.1000
`0.1471
`0.5000
`
`The composition is prepared according to the procedure in
`Example 1.
`We claim:
`1. An aqueous nasal spray composition comprising:
`a medicament selected from the group consisting of
`0.001—2% by weight/volume of chlorpheniramine
`maleate, 0.001—0.2% by weight/volume of oxymetazo-
`line hydrochloride, or mixtures thereof;
`0.50 to 15.00% by weight/volume of a water soluble
`polymer selected from the group consisting of polyvi-
`nylpyrrolidone having an average molecular weight of
`about 10,000 to 360,000 and mixtures thereof;
`0.00 to 15 .00% by weight/volume of polyethylene glycol;
`0.00 to 10.00% by weight/volume of moisturizing agent
`other than polyethylene glycol;
`0.00 to 10.00% by weight/volume of an antioxidant;
`0.001 to 0.3% by weight/volume of an antimicrobial
`preservative;
`0.00 to 5.00% by weight/volume of an aromatic alcohol;
`a sufficient amount of a pharmaceutically acceptable
`buffer to maintain the pH of the composition within the
`range of about 4.0 to 8.0; and
`QS water.
`2. The aqueous nasal spray composition of claim 1,
`wherein the medicament is oxymetazoline hydrochloride.
`3. The aqueous nasal spray composition of claim 1,
`wherein the medicament is chlorpheniramine maleate.
`4. The aqueous nasal spray composition of claim 1,
`comprising 0.50 to 2.5% by weight/volume of the water
`soluble polymer.
`5. The aqueous nasal spray composition of claim 1,
`wherein the medicament is oxymetazoline hydrochloride,
`the moisturizing agent is propylene glycol, the antioxidant is
`disodium EDTA, the antimicrobial preservative is benzalko-
`nium chloride, the aromatic alcohol is benzyl alcohol, and
`the buffer is a phosphate buffer.
`6. An aqueous nasal spray composition comprising:
`a medicament selected from the group consisting of
`0.001—2% by weight/volume of chlorpheniramine
`maleate, 0.001—0.2% by weight/volume of oxymetazo-
`line hydrochloride, or mixtures thereof;
`0.50 to 2.5% by weight/volume of a water soluble poly-
`mer selected from the group consisting of polyvi-
`nylpyrroline having an average molecular weight of
`about 10,000 to 360,000 and mixtures thereof;
`0.5 to 10.00% by weight/volume of polyethylene glycol;
`1.00 to 4.00% by weight/volume of moisturizing agent
`other than polyethylene glycol;
`
`8
`0.01 to 0.05% by weight/volume of an antioxidant;
`0.02 to 0.025% by weight/volume of an antimicrobial
`preservative;
`0.20 to 3.00% by weight/volume of an aromatic alcohol;
`a sufficient amount of a pharmaceutically acceptable
`buffer to maintain the pH of the composition within the
`range of about 4.0 to 8.0; and
`QS water.
`7. The aqueous nasal spray composition of claim 6,
`wherein the medicament is oxymetazoline hydrochloride.
`8. The aqueous nasal spray composition of claim 6,
`wherein the medicament is chlorpheniramine maleate.
`9. The aqueous nasal spray composition of claim 6,
`wherein the medicament is oxymetazoline hydrochloride,
`the moisturizing agent is propylene glycol, the antioxidant is
`disodium EDTA, the antimicrobial preservative is benzalko-
`nium chloride, the aromatic alcohol is benzyl alcohol, and
`the buffer is a phosphate buffer.
`10. An aqueous nasal spray composition comprising:
`a medicament selected from the group consisting of
`0.001—2% by weight/volume of chlorpheniramine
`maleate, 0.001—0.2% by weight/volume of oxymetazo-
`line hydrochloride, or mixtures thereof;
`1.00 to 1.50% by weight/volume of a water soluble
`polymer selected from the group consisting of polyvi-
`nylpyrrolidone having an average molecular weight of
`about 10,000—360,000 and mixtures thereof;
`2.5 to 5.0% by weight/volume of polyethylene glycol;
`1.50 to 3.50% by weight/volume of moisturizing agent
`other than polyethylene glycol;
`0.015 to 0.030% by weight/volume of an antioxidant;
`0.02 to 0.025% by weight/volume of an antimicrobial
`preservative;
`0.25 to 1.00% by weight/volume of an aromatic alcohol;
`a sufficient amount of a pharmaceutically acceptable
`buffer to maintain the pH of the composition within the
`range of about 4.0 to 8.0; and
`QS water.
`11. The aqueous nasal spray composition of claim 10,
`wherein the medicament is oxymetazoline hydrochloride.
`12. The aqueous nasal spray composition of claim 10,
`wherein the medicament is chlorpheniramine maleate.
`13. The aqueous nasal spray composition of claim 10,
`wherein the medicament is oxymetazoline hydrochloride,
`the moisturizing agent is propylene glycol, the antioxidant is
`disodium EDTA, the antimicrobial preservative is benzalko-
`nium chloride, the aromatic alcohol is benzyl alcohol, and
`the buffer is a phosphate buffer.
`14. An aqueous nasal spray composition comprising:
`0.001 to 0.2% by weight/volume of oxymetazoline hydro-
`chloride;
`0.5 to 15% by weight/volume of a water soluble polymer
`selected from the group consisting of polyvinylpyrroli-
`done having an average molecular weight of about
`10,000 to 360,000 and mixtures thereof;
`0.00 to 15% by weight/volume of polyethylene glycol;
`0.00 to 10% by weight/volume of propylene glycol;
`0.00 to 10% by weight/volume of disodium EDTA;
`0.001 to 0.3% by weight/volume of benzalkonium chlo-
`ride;
`0.00 to 5% by weight/volume of benzyl alcohol;
`a phosphate; and
`QS water.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Page 5
`
`

`
`US 6,316,483 B1
`
`9
`15. An aqueous nasal spray composition comprising:
`0.001 to 0.2% by Weight/Volume of oxyrnetazoline hydro-
`chloride; and
`0.50 to 15.00% by Weight/Volume of a Water soluble
`polymer selected from the group consisting of polyVi-
`
`10
`nylpyrrolidone having an average molecular Weight of
`ab011t 10,000 t0 360,000 and mixtures th€r€0f.
`
`*
`
`*
`
`*
`
`*
`
`*
`
`Page 6