(12) United States Patent
`Haslwanter et al.
`
`I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US006565832Bl
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,565,832 Bl
`May 20, 2003
`
`(54) SPRAY COMPOSITION WITH REDUCED
`DRIPPING
`
`(75)
`
`Inventors: Joseph A. Haslwanter, Germantown,
`TN (US); William J. McLaughlin,
`Germantown, TN (US); David M.
`Oakley, Germantown, TN (US); Kurt
`G. Van Scoik, Germantown, TN (US)
`
`(73) Assignee: Schering-Plough HealthCare
`Products, Inc., Memphis, TN (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.
`
`(21) Appl. No.: 09/494,574
`
`(22) Filed:
`
`Jan. 31, 2000
`
`Int. Cl.7 ............................. A61K 9/12; A61K 9/08
`(51)
`(52) U.S. Cl. ...................... 424/45; 424/78.04; 424/434;
`514/853
`(58) Field of Search ................................ 424/45, 78.04,
`424/78.08, 601, 434; 514/912, 853, 937
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`5,854,269 A * 12/1998 Haslwanter et al.
`5,897,858 A * 4/1999 Haslwanter et al.
`5,976,573 A * 11/1999 Kim
`6,368,616 Bl * 4/2002 Doi ............................ 424/434
`
`* cited by examiner
`
`Primary Examiner-Michael G. Hartley
`Assistant Examiner-M. Haghighatian
`(74) Attorney, Agent, or Firm-Robert A Franks
`
`(57)
`
`ABSTRACT
`
`An aqueous-based sprayable composition comprises a thera(cid:173)
`peutic or palliative agent, water and a mixture of microc(cid:173)
`rystalline cellulose and alkali metal carboxyalkylcellulose.
`In one embodiment, the composition is a non-Newtonian
`nasal spray exhibiting a very rapid viscosity recovery upon
`removal of shear forces.
`
`5 Claims, 2 Drawing Sheets
`
`105 .---~---,~~~~~~~~~~~~~~~~~~~~.---~~~~~o
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`0.0
`5.0
`100
`15.0
`20.0
`25.0
`30.0
`35.0
`40.0
`45.0
`50.0
`
`Exhibit 1155
`IPR2017-00807
`ARGENTUM
`
`000001
`
`

`

`U.S. Patent
`
`May 20, 2003
`
`Sheet 1 of 2
`
`US 6,565,832 Bl
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`

`

`U.S. Patent
`
`May 20, 2003
`
`Sheet 2 of 2
`
`US 6,565,832 Bl
`
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`000003
`
`

`

`1
`SPRAY COMPOSITION WITH REDUCED
`DRIPPING
`
`US 6,565,832 Bl
`
`INTRODUCTION TO THE INVENTION
`The present invention relates to the field of fluid compo(cid:173)
`sitions for application to the body, and more particularly to
`spray compositions which have a reduced tendency to run or
`drip.
`Nasal sprays have been used for many years by persons
`suffering from nasal disorders, such as infections or allergic
`manifestations. Among the pharmaceutical agents com(cid:173)
`monly delivered intranasally are antihistamines, antiinflam(cid:173)
`matory drugs, decongestants, antimuscarinics, antibiotics,
`anesthetics and moisturizers. In addition, it is possible to 15
`deliver agents intranasally to achieve systemic effects
`through absorption across the well-vascularized mucosal
`membranes; certain vaccines, analgesics and other prophy(cid:173)
`lactic or therapeutic substances can be efficiently adminis(cid:173)
`tered in this manner.
`Various spray compositions are also known for applica(cid:173)
`tion other than intranasally, such as breath freshener and
`analgesic sprays for the mouth and pharynx and antiseptic
`sprays for skin application of medicinal or cosmetic com(cid:173)
`positions.
`A common problem with spray administration is a low
`efficiency of the active agent, since the structure of body
`cavities and parts does not typically facilitate retention of the
`applied formulation. This is particularly the case for
`aqueous-base nasal spray formulations, which must have
`sufficient fluidity to be dispensed by a pump device or a
`squeeze-type spray bottle, but which can simply drain from
`the nose or pass through the nose and into the pharynx while,
`or immediately after, being sprayed. Moreover, due to
`ciliation of the nasal passages and movement of air through
`the nose, even materials applied in particulate form, such as
`by a pressurized metered dose inhaler or a powdered drug
`inhaler, are rapidly cleared from the nose. Several of the
`possible active agents or other formulation components have
`a quite unpleasant taste, so it is desirable to minimize the
`amount of the formulation which is not retained within the
`nose for at least the minimum time required to obtain the
`desired effect. Due to swallowing of much of the formula(cid:173)
`tion which enters the oropharyngeal area, a large portion of
`the active agent introduced into the nose is generally ren(cid:173)
`dered unavailable for its intended use.
`Aqueous materials sprayed onto the oral, rectal or vaginal
`mucosa, or onto the skin, similarly have a tendency to run or
`drip, and therefore frequently are not retained in a desired
`location for sufficient time to accomplish the desired
`function, which may involve absorption of an active agent
`by the underlying tissues for a local or systemic effect.
`International Patent Application WO 94/05330 describes
`a nasal spray product that forms a gel upon contact with ss
`mucous membranes, which product contains a crosslinked
`acrylic acid-based polymer. The product is alleged to exhibit
`a reduced tendency for "roll-back," where liquid exits the
`nose after spray application.
`The product Nasacor™ AQ nasal spray is an aqueous
`suspension of particles of the corticosteroid drug triamcino(cid:173)
`lone acetonide, and contains about 2 percent by weight of a
`mixture of microcrystalline cellulose and carboxymethyl(cid:173)
`cellulose sodium, as a suspending agent. Such suspensions
`are described in U.S. Pat. No. 5,976,573.
`The product Vancenase™ AQ nasal spray is an aqueous
`suspension of the corticosteroid drug beclomethasone dipro-
`
`45
`
`2
`pionate monohydrate, containing about 1.5 percent by
`weight of a mixture of microcrystalline cellulose and car(cid:173)
`boxymethylcellulose sodium, as a suspending agent.
`The product Nasonex™ nasal spray is an aqueous sus-
`s pension of the corticosteroid drug mometasone furoate
`monohydrate, containing about 2 percent by weight of a
`mixture of microcrystalline cellulose and carboxymethyl(cid:173)
`cellulose sodium, as a suspending agent.
`It would be desirable to provide an aqueous composition
`10 that can be made to have a viscosity sufficiently low to
`permit spraying with a standard pump mechanism or
`squeeze-type spray bottle, but which then rapidly exhibits a
`significant viscosity increase to retain the composition at the
`application site.
`
`SUMMARY OF THE INVENTION
`
`The present invention provides an aqueous-based spray(cid:173)
`able composition containing a therapeutic or palliative
`agent, water and a mixture of microcrystalline cellulose and
`20 alkali metal carboxyalkylcellulose. The composition is a
`non-Newtonian, or thixotropic, fluid, exhibiting a reduced
`apparent viscosity while being subjected to shear forces, but
`a high apparent viscosity while at rest; this property permits
`application by spraying with readily available pump spray
`25 devices or squeeze-type spray bottles immediately following
`the application of a shearing force (such as those created by
`vigorously shaking the product container), but causes the
`sprayed material to remain at least temporarily relatively
`immobile on mucosal membranes or the skin. The preferred
`30 embodiments have a very rapid rate of viscosity recovery,
`following withdrawal of the shearing force.
`The invention can be used to prepare many types of spray
`compositions, such as those for application to mucous
`35 membranes or the skin. In a particularly preferred form, the
`invention is an aqueous nasal spray containing a topically
`active decongestant.
`
`40
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1 is a graphical representation of the results of the
`experiment described in Example 4.
`FIG. 2 is a graphical representation of the results of the
`experiment described in Example 5.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`The essential components of the composition of the
`present invention are water, a therapeutic or palliative agent
`and a mixture of microcrystalline cellulose and an alkali
`so metal carboxyalkylcellulose. It is contemplated that the
`composition will be useful for delivering agents by spraying;
`it is an advantage of the invention that the composition, after
`spraying, has a minimal tendency to drip or run from the
`surface to which it is applied.
`Typically, purified water, such as that treated by
`distillation, deionization or reverse osmosis techniques will
`be used, it generally being desired to minimize formulation
`characteristic variations which may occur when the water
`supply is not very consistent in its chemical makeup. Pre-
`60 ferred waters include those having the specifications of the
`official monograph for "Purified Water" in the current
`United States Pharmacopeia, published by United States
`Pharmacopeial Convention, Inc., Rockville, Md. U.S.A. In
`those instances where microbial contamination must be
`65 prevented, such as for antiseptic skin sprays, sterile water
`will be used and any of the customary preservatives will be
`added.
`
`000004
`
`

`

`US 6,565,832 Bl
`
`5
`
`20
`
`3
`Numerous classes of pharmaceutical active agents are
`suitable for inclusion in the thixotropic formulation of the
`invention. Agents for delivery intranasally include
`antihistamines, antiinflammatory drugs, decongestants,
`antimuscarinics, antibiotics, anesthetics and moisturizers.
`Orally delivered agents include antibiotics, analgesics, anes(cid:173)
`thetics and moisturizers. Agents which are delivered vagi(cid:173)
`nally or rectally include antiemetics, antibiotics (including
`antimycotic agents), analgesics and anesthetics. For topical
`application to the skin, useful active agents include sun(cid:173)
`screening agents, local anesthetics and antimicrobials. These
`lists are not intended to be exhaustive, as many other types
`of active agents can beneficially be incorporated into the
`inventive formulations. Frequently, it will be desired to
`incorporate a mixture of two or more active agents, some(cid:173)
`times including more than one class of such agents, in a
`composition.
`Particularly efficacious in the nasal spray compositions of
`the present invention are the sympathomimetic amine nasal
`decongestants. Those currently approved for topical use in
`the United States include, without limitation, levmetamfe(cid:173)
`tamine (also known as 1-desoxyephedrine ), ephedrine,
`ephedrine hydrochloride, ephedrine sulfate, naphazoline
`hydrochloride, oxymetazoline hydrochloride, phenylephrine
`hydrochloride, propylhexedrine and xylometazoline hydro(cid:173)
`chloride. Levmetamfetamine and propylhexidrine are typi(cid:173)
`cally administered by inhalation, being dispersed in air, so
`are candidates for pressurized aerosol formulation, while the
`other compounds are usually administered topically in aque(cid:173)
`ous solutions or jellies, in concentrations differing for the
`individual drugs, but typically not exceeding about 1 percent
`by weight.
`Specific drugs that may be incorporated when the com(cid:173)
`position is intended to relieve oropharyngeal discomfort,
`such as sore throat, cold or canker sores, painful gums and
`other conditions are topical anesthetics such as phenol,
`hexylresorcinol, salicyl alcohol, benzyl alcohol, dyclonine,
`dibucaine, benzocaine, buticaine, cetylpyridinium chloride,
`diperidon, clove oil, menthol, camphor, eugenol and others.
`Similarly, drugs that may be incorporated for application to
`the skin for relieving discomfort include lidocaine,
`benzocaine, tetracaine, dibucaine, pramoxine,
`diphenhydramine, benzyl alcohol, hydrocortisone,
`betamethasone, mometasone and others.
`Mixtures of microcrystalline cellulose and an alkali metal
`carboxyalkylcellulose are commercially available, the mix(cid:173)
`ture presently preferred for use in this invention being sold
`by FMC Corporation, Philadelphia, Pa. U.S.A. as Avicel™
`RC-591. This material contains approximately 89 weight
`percent microcrystalline cellulose and approximately 11 50
`weight percent sodium carboxymethylcellulose, and is
`known for use as a suspending agent in preparing various
`pharmaceutical suspensions and emulsions. However, there
`previously has been no reported application for this material
`in compositions which otherwise have no suspended 55
`particulates, i.e., which compositions are solutions. The
`compositions of the present invention contain at least about
`2.5 weight percent of the cellulose/carboxyalkylcellulose
`compound mixture, generally not exceeding about 10 weight
`percent to avoid producing high viscosities which impede 60
`spraying with the usual devices. Preferably, about 2.5 to
`about 5 percent of the mixture will be included. More
`preferably, the amount will be about 2.5 to about 3.5 weight
`percent.
`A closely related mixture is available from the same
`source as Avicel TM RC-581, having the same bulk chemical
`composition as the RC-591, and this material is also useful
`
`4
`in the invention. Microcrystalline cellulose and alkali metal
`carboxyalkylcellulose are commercially available
`separately, and can be mixed in desired proportions for use
`in the invention, with the amount of microcrystalline cellu-
`lose preferably being between about 85 and about 95 weight
`percent of the mixture for both separately mixed and
`co-processed mixtures. However, performance of the inven(cid:173)
`tive composition appears to generally be better when the
`co-processed mixtures are used.
`10 When the compositions of the invention are intended for
`application to sensitive mucosal membranes, it will usually
`be desirable to adjust the pH to a relatively neutral value,
`using an acid or base, unless the natural pH already is
`suitable. In general, pH values about 4 to about 8 are
`15 preferred for tissue compatibility; the exact values chosen
`should also promote chemical and physical stability of the
`composition. In some instances, buffering agents will be
`included to assist with maintenance of selected pH values;
`typical buffers are well known in the art and include, without
`limitation thereto, phosphate, citrate and borate salt systems.
`Depending on the intended application, it may be desir(cid:173)
`able to incorporate up to about 10 percent by weight, more
`typically about 0.5 to about 5 weight percent, of an addi(cid:173)
`tional rheology-modifying agent, such as a polymer or other
`25 material. Useful materials include, without limitation
`thereto, sodium carboxymethyl cellulose, algin,
`carageenans, carbomers, galactomannans, hydroxypropyl
`methylcellulose, hydroxypropyl cellulose, polyethylene
`glycols, polyvinyl alcohol, polyvinylpyrrolidone, sodium
`30 carboxymethyl chitin, sodium carboxymethyl dextran,
`sodium carboxymethyl starch and xanthan gum. Combina(cid:173)
`tions of any two or more of the foregoing are also useful.
`The compositions may further contain any of a number of
`optional components, such as humectants, preservatives and
`35 aromatic substances. Humectants, which are hygroscopic
`materials such as glycerin, a polyethylene or other glycol, a
`polysaccharide and the like act to inhibit water loss from the
`composition and may add moisturizing qualities. Useful
`aromatic substances include camphor, menthol, eucalyptol
`40 and the like, and fragrances. Preservatives are typically
`incorporated to establish and maintain a freedom from
`pathogenic organisms; representative components include
`benzyl alcohol, methylparaben, propylparaben,
`butylparaben, chlorobutanol, phenethyl alcohol (which also
`45 is a fragrance additive), phenyl mercuric acetate and ben(cid:173)
`zalkonium chloride.
`The more simple techniques commonly used to determine
`rheological properties of fluid compositions, including the
`Brookfield rotating kinematic viscometer which measures
`torque transmitted through a sample using a rotating spindle,
`do not yield the most meaningful information for non-
`Newtonian fluids such as those of this invention. Since the
`viscosity of the thixotropic composition varies inversely
`according to the magnitude of shear force being applied, and
`the viscosity increases over time following withdrawal of
`the shear force, it is more useful to measure and compare
`complex viscosity. A mathematical derivation of complex
`viscosity can be found in H. A. Barnes et al.,Anlntroduction
`to Rheology, Elsevier, N.Y. 1989, particularly at pages
`46-48. Complex viscosity from a oscillatory applied shear is
`defined by these authors at page 48 as being: "the ratio of the
`shear stress ... to the rate of shear. ... "Units for expressing
`complex viscosity (typically represented by the symbol ri*)
`are in Pascal seconds (Pa.s.), equivalent to newton seconds/
`65 meter2 in the International System of Units.
`The composition of the invention has a shear viscosity
`sufficiently low to permit spraying with the customary
`
`000005
`
`

`

`US 6,565,832 Bl
`
`5
`pumps or squeeze bottles commonly used to deliver prod(cid:173)
`ucts such as nasal sprays. It should be noted that this shear
`viscosity frequently will not be the minimum viscosity
`attainable under shear conditions, since it is expected that
`sprayability will be achieved from a more or less vigorous 5
`shaking by the user, immediately prior to dispensing. Dif(cid:173)
`ferent populations have differing physical abilities to impart
`shear to the product, so candidate compositions will neces(cid:173)
`sarily be tested with various spray devices, to determine
`which combination will be satisfactory for the intended 10
`purpose. Further, different amounts of the mixture of micro(cid:173)
`crystalline cellulose and alkali metal carboxyalkylcellulose
`(and varying ratios of the components of this mixture) may
`be used, as well as the incorporation of other rheology
`modifiers, to obtain a desired viscosity behavior.
`The invention will be further described by means of the
`following examples, which are not intended to limit the
`scope of the invention, as defined by the appended claims,
`in any manner. In the examples, as elsewhere in this
`specification, chemical substances are generally identified, 20
`whenever possible, by their adopted names, such as are
`given in J. A. Wenninger et al., Eds., International Cosmetic
`Ingredient Dictionary and Handbook, Seventh Ed., The
`Cosmetic, Toiletry and Fragrance Association, Washington,
`D.C., U.S.A., 1997. Percentages are expressed on a weight 25
`basis, unless the context clearly indicates otherwise. The
`mention of any specific drug substance in this specification
`or in the claims is intended to encompass not only the base
`drug, but also pharmaceutically acceptable salts, esters,
`hydrates and other forms of the drug. Where a particular salt
`or other form of a drug is mentioned, it is contemplated that
`other salts or forms can be substituted.
`
`15
`
`EXAMPLE 1
`A nasal spray composition is prepared using the following 35
`ingredients (amounts expressed in grams), together with
`sufficient purified water to make a total of 1000 grams.
`
`Ingredient
`
`40
`
`6
`(d) The solution of (c) is added to the dispersion of (a);
`( e) in another vessel, the disodium EDTA is dissolved in
`about 12 grams of water and, after a solution is
`obtained, the sodium phosphates are added and dis(cid:173)
`solved;
`(t) the solution of (e) is added to the dispersion of (d);
`(g) to about 5 grams of water in a separate vessel is added
`the oxymetazoline hydrochloride and the mixture is
`stirred to obtain a solution;
`(h) the solution of (g), the benzyl alcohol, the benzalko(cid:173)
`nium chloride and the lemon flavor are sequentially
`added to the dispersion of (t), with a period of stirring
`being completed between additions;
`(i) additional water is added to achieve a batch of 1000
`grams and the product is thoroughly stirred; and
`G) the entire batch is passed through the high-shear
`disperser to ensure that any coagulated particles are
`re-dispersed.
`
`EXAMPLE 2
`
`Nasal spray compositions are prepared in accordance with
`the invention, using the general procedure of the preceding
`example and the following ingredients (where amounts are
`weight percentages):
`
`3o Ingredient
`
`Water
`Oxymetazoline hydrochloride
`Avicel ™-591
`Polyvinylpyrrolidone*
`PEG-32**
`Sodium phosphate, dibasic
`Sodium phosphate, monobasic
`Disodium EDTA
`Benzalkonium chloride, 17% aq. solution
`Benzyl alcohol
`Lemon flavor
`Glycerin
`Propylene glycol
`Camphor
`Menthol
`Eucalyptol
`
`A
`
`B
`
`c
`
`89.7229 90.2279 89.7229
`0.05
`0.05
`0.05
`3
`3
`3
`3
`3
`3
`5
`5
`5
`0.0975
`0.0975
`0.0975
`0.5525
`0.5525
`0.5525
`0.03
`0.03
`0.03
`0.1471
`0.1471
`0.1471
`0.25
`0.35
`0.3
`0.15
`0.5
`
`0.009
`0.027
`0.009
`
`0.5
`0.02
`0.06
`0.02
`
`Oxymetazoline hydrochloride
`Avicel RC-591
`Polyvinylpyrrolidone*
`PEG-32**
`Sodium phosphate, dibasic
`Sodium phosphate, monobasic
`Disodium EDTA
`Benzalkonium chloride, 17% aq. solution
`Benzyl alcohol
`Lemon flavor
`
`0.4878
`29.2683
`29.2683
`48.7805
`0.9512
`5.3902
`0.2927
`1.4351
`2.439
`1.4634
`
`*Plasdone TM K29-32 sold by International Specialty Products, Wayne,
`New Jersey U.S.A.
`**CARBOWAX TM PEG 1450 sold by Union Carbide Corporation,
`Houston, Texas U.S.A.
`
`45 *Plasdone TM K29-32 sold by International Specialty Products, Wayne,
`New Jersey U.S.A.
`**CARBOWAX TM PEG 1450 sold by Union Carbide Corporation,
`Houston, Texas U.S.A.
`
`50
`
`EXAMPLE 3
`
`Nasal spray compositions are prepared in accordance with
`the invention, using the general procedure of preceding
`Example 1 and the following ingredients (where amounts
`55 are weight percentages):
`
`Ingredient
`
`D
`
`E
`
`F
`
`G
`
`Water
`Oxymetazoline hydrochloride
`Avicel ™-591
`Polyvinylpyrrolidone*
`PEG-32**
`Sodium phosphate, dibasic
`Sodium phosphate, monobasic
`Disodium EDTA
`
`95.8272
`0.0488
`2.9268
`
`90.9492
`0.0488
`2.9268
`
`0.0951
`0.539
`0.0293
`
`4.878
`0.0951
`0.539
`0.0293
`
`92.9004 88.5102
`0.0488
`0.0488
`2.9268
`2.439
`2.9268
`2.9268
`4.878
`0.0951
`0.539
`0.0293
`
`0.0951
`0.539
`0.0293
`
`The composition is prepared as follows:
`(a) the Avicel RC-591 is dispersed in about 725 grams of
`the water, by means of slow addition to the vigorously
`stirred water and circulation of the dispersion through
`a high-shear disperser for at least 60 minutes after all of 60
`the Avicel material has been added, to form a uniform
`dispersion;
`(b) in a separate vessel, the polyvinylpyrrolidone is dis(cid:173)
`solved in about 85 grams of the water and stirred until
`a clear solution is obtained;
`(c) the polyethylene glycol is added to the solution of (b)
`and stirred until a clear solution is obtained;
`
`65
`
`000006
`
`

`

`US 6,565,832 Bl
`
`7
`
`-continued
`
`Ingredient
`
`D
`
`E
`
`F
`
`G
`
`Benzalkonium chloride, 17%
`aq. solution
`Benzyl alcohol
`Lemon flavor
`
`0.1435
`
`0.1435
`
`0.1435
`
`0.1435
`
`0.2439
`0.1463
`
`0.2439
`0.1463
`
`0.2439
`0.1463
`
`0.2439
`0.1463
`
`*Plasdone TM K29-32 sold by International Specialty Products, Wayne,
`New Jersey U.S.A.
`**CARBOWAX TM PEG 1450 sold by Union Carbide Corporation,
`Houston, Texas U.S.A.
`
`EXAMPLE 4
`
`5
`
`Commercially available nasal spray compositions are
`tested against the composition of preceding Example 1, to
`identify differences in their dripping potentials. In the test,
`borosilicate glass test tubes are weighed, then clamped in an
`inverted vertical position. The nasal spray bottle is weighed,
`placed under the mouth of the test tube, sprayed twice and
`then immediately removed. After 60 seconds, the test tube is
`turned vertically to position the mouth at the top and is
`weighed to quantify the amount of nasal spray that did not
`drip out. The nasal spray bottle is weighed to determine the
`amount delivered by the two spray actuations, and the
`percentage of the delivered dose remaining in the test tube
`is calculated.
`Results are as shown in the following table and in the
`graph of FIG. 1, where bars "A" and "B" represent the
`percentage of sprayed material remaining in the tube for two 30
`different preparations of the composition of Example 1. The
`remaining legends of the graph identify the tested commer(cid:173)
`cially available compositions. Each composition is tested in
`duplicate, and the results of each of the two trials for a
`product are shaded differently in the graph.
`The Afrin™ Extra Moisturizing Nasal Spray product
`contains 0.05 weight percent oxymetazoline, in addition to
`benzalkonium chloride, disodium EDTA, povidone, sodium
`phosphate dibasic, sodium phosphate monobasic, glycerin,
`polyethylene glycol 1450, propylene glycol and water. This
`product, sold in a "squeeze-type" spray bottle, is transferred
`to a pump spray bottle identical to those used for the
`Example 1 compositions, for this test. All other commercial
`products are tested in their original pump spray bottles.
`
`35
`
`8
`ing force. The experiment utilizes a dynamic stress rheom(cid:173)
`eter Model SR-5000 available from Rheometric Scientific,
`Inc., Piscataway, N.J. U.S.A., the sample being contained in
`a cone and plate fixture. The instrument is set to apply a
`shearing stress to the sample that begins at zero and ramps
`upward to 1000 dynes/cm2 during a 5 second period. The
`stress ramps down to 5 dynes/cm2 during the next 2 seconds,
`then from 5 to 4 dynes/cm2 during the following 50 seconds.
`A graphical comparison of the complex viscosities of the
`composition of Example 1 (upper curve) and of the com-
`10 mercial NASONEX™ nasal spray, containing 2 weight
`percent of a mixture of microcrystalline cellulose and car(cid:173)
`boxymethylcellulose sodium, (lower curve) is shown as
`FIG. 2, where the y-axis is complex viscosity and the x-axis
`is time in seconds during the period where applied stress is
`15 ramping downward from 5 to 4 dynes/cm2
`.
`Referring to FIG. 2, it can be seen that at 20 seconds the
`Example 1 composition has recovered its complex viscosity
`in an amount approximately an order of magnitude greater
`than that recovered by the NASONEX composition. Thus,
`20 the higher concentration of a mixture of microcrystalline
`cellulose and carboxymethylcellulose sodium gives the
`Example 1 composition a greatly reduced tendency to flow
`after spraying.
`These graphical results may constitute an explanation for
`25 the higher amount of Nasonex product that drips from the
`tube in the experiment of the immediately preceding
`example.
`What is claimed is:
`1. A nasal spray composition comprising water, oxymeta-
`zoline hydrochloride, about 2.5 to about 3.5 weight percent
`of a mixture of microcrystalline cellulose and an alkali metal
`carboxyalkylcellulose, and about 0.5 to about 5 weight
`percent of polyvinylpyrrolidone, wherein complex viscosity
`of the composition increases to at least about 10 times a
`minimum complex viscosity of the composition as measured
`under high shear conditions, within about 20 seconds after
`the high shear conditions terminate.
`2. The nasal spray composition of claim 1, wherein the
`alkali metal carboxyalkylcellulose is sodium carboxymeth(cid:173)
`y !cellulose.
`3. The nasal spray composition of claim 2, wherein
`microcrystalline cellulose comprises between about 85 and
`about 95 percent by weight of the mixture with sodium
`carboxymethylcellulose.
`1
`~
`4. A nasal spray composition comprising: water; a nasa
`decongestant comprising oxymetazoline hydrochloride;
`about 2.5 to about 3.5 percent by weight of a mixture of
`microcrystalline cellulose and an alkali metal carboxyalky(cid:173)
`lcellulose; and about 0.5 to about 5 percent by weight of a
`rheology-modifying polymer; wherein complex viscosity of
`the composition increases to at least about 10 times a
`minimum complex viscosity of the composition as measured
`under high shear conditions, within about 20 seconds after
`the high shear conditions terminate.
`5. A nasal spray composition comprising: water, a nasal
`decongestant comprising oxymetazoline hydrochloride;
`about 2.5 to about 3.5 percent by weight of a mixture of
`microcrystalline cellulose and an alkali metal carboxyalky(cid:173)
`lcellulose; and about 0.5 to about 5 percent by weight of a
`60 rheology-modifying polymer comprising polyvinylpyrroli(cid:173)
`done; wherein complex viscosity of the composition
`increases to at least about 10 times a minimum complex
`viscosity of the composition as measured under high shear
`conditions, within about 20 seconds after the high shear
`65 conditions terminate.
`
`40
`
`50
`
`55
`
`Product
`
`mg Sprayed
`
`mg Remaining
`
`% Remaining
`
`Example 1, "A"
`214.1, 214.4
`Example 1, "B"
`217.5, 219.8
`Nasonex TM
`204.3, 202.4
`Vancenase AQ TM 202.9, 214.8
`Nasacort AQ TM
`196.9, 195.5
`Afrin TM Extra
`207.8, 208.9
`Moisturizing
`
`212.6, 213.5
`216.0, 219.4
`162.9, 158.9
`132.6, 132.5
`97.4, 103.8
`55.6, 63.9
`
`99.3, 99.6
`99.3, 99.8
`79.7, 78.5
`65.4, 61.7
`49.5, 53.1
`26.8, 30.6
`
`It is clear that the products of Example 1 have a signifi(cid:173)
`cantly lower dripping potential than any other tested prod(cid:173)
`uct. Moreover, since no dripping was visible for the
`Example 1 compositions, it is possible that the small dif(cid:173)
`ferences between amounts of material sprayed and material
`remaining are due to evaporation of contained water during
`the course of the experiment.
`
`EXAMPLE 5
`An experiment is performed to measure the rate at which
`viscosity is recovered, upon termination of an applied shear-
`
`* * * * *
`
`000007
`
`