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`known by those of ordinary skill
`
`in the art for use in preserved formulations, or a
`
`combination thereof.
`
`As used herein, the term “alkalizing agent” is intended to mean a compound used
`
`to provide alkaline medium, such as for product stability. Such compounds include, by
`
`way of example and without
`
`limitation, ammonia solution, ammonium carbonate,
`
`diethanolamine, monoethanolamine, potassium hydroxide,
`
`sodium borate,
`
`sodium
`
`carbonate,
`
`sodium bicarbonate,
`
`sodium hydroxide,
`
`triethanolamine, diethanolamine,
`
`organic amine base, alkaline amino acids and trolamine and others known to those of
`
`ordinary skill in the art.
`
`As used herein, the term “acidifying agent” is intended to mean a compound used
`
`to provide an acidic medium for product stability. Such compounds include, by way of
`
`example and without limitation, acetic acid, acidic amino acids, citric acid, fumaric acid
`
`and other alpha hydroxy acids, hydrochloric acid, ascorbic acid, phosphoric acid, sulfuric
`
`acid, tartaric acid and nitric acid and others known to those of ordinary skill in the art.
`
`Inclusion of a preservative in the solution is optional, since the formulation is self—
`
`preseryed by SAE—CD depending upon its concentration in solution.
`
`If a conventional
`
`preservative is included in the composition, the corticosteroid, such as budesonide, can
`
`have a greater binding with the SAE-CD than does a conventional preservative.
`
`Nonetheless, a preservative can be further included in the formulation if desired.
`
`Preservatives can be used to inhibit microbial growth in the compositions. The amount of
`
`preservative is generally that which is necessary to prevent microbial growth in the
`
`composition for a storage period of at least six months. As used herein, a preservative is a
`
`compound used to at least reduce the rate at which bioburden increases, but preferably
`
`maintains bioburden steady or reduces bioburden after contamination has occurred. Such
`
`compounds
`
`include,
`
`by
`
`way
`
`of
`
`example
`
`and
`
`without
`
`limitation,
`
`3—(trimethoxysilyl)propyldimethyloctadecylammonium chloride,
`
`stearyldimethylbenzyl—
`
`ammonium chloride, 6-acetoxy-2,4-dimethylmetadioxane, alkali metal
`
`sorbates and
`
`mixtures, ammonium sorbate, BAC, benzalkonium chloride, benzethonium chloride,
`
`benzoic acid (and salts), benzyl alcohol, boric acid, bronopol, butyl parabens, C.sub.l6
`
`benzalkonium halide compounds, cetrimide, cetyldimethylbenzylammonium chloride,
`
`cetylpyridinium bromide, cetylpyridinium chloride, chlorbutanol, chlorhexidine, chlorine
`
`dioxide, chlorite components, Chlorobutanol, chlorocresol, chlorohexidine gluconate,
`
`chlorohexidine
`
`hydro chloride,
`
`cres 01,
`
`di stearyldimethylammoniu m
`
`chloride,
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`dodecylguanidine, dodecylguanidine hydrochloride, domiphen bromide, ethanol, ethyl
`
`parabens,
`
`guanidines,
`
`lauroylisoquinolium bromide, metacresol, Methylparaben,
`
`myristylgamma picolinium chloride, paraben mixtures, phenol, phenol derivative,
`
`phcnoxycthanol, phcnylcthanol, phcnylmcrcuric
`
`acctatc,
`
`phcnylmcrcuric
`
`nitratc,
`
`phenylmercuric salts, polyhexmethylenebiguanidine hydrochloride, polymeric quaternary
`
`ammonium compounds, potassium sorbate, propylparaben, quaternary ammonium
`
`alkylene glycol phospholipid derivatives, quaternary ammonium salts, propyl parabens,
`
`sodium sorbate,
`
`sorbic
`
`acid
`
`(and
`
`salts),
`
`stearylpentaethoxyammonium chloride,
`
`stearyltolylmethyl-ammonium chloride, sulfites inorganic, thiomersal, thymol,and others
`
`known to those of ordinary skill in the art.
`
`As used herein, the term “antioxidant” is intended to mean an agent that inhibits
`
`oxidation and thus is used to prevent the deterioration of preparations by the oxidative
`
`proccss. Such compounds includc, by way of example and without limitation, acctonc,
`
`potassium metabisulfite, potassium sulfite, ascorbic acid, ascorbyl palmitate, citric acid,
`
`butylated
`
`hydroxyanisole,
`
`butylated
`
`hydroxytoluene,
`
`hypophophorous
`
`acid,
`
`monothioglycerol, propyl gallate, sodium ascorbate, sodium citrate, sodium sulfide,
`
`sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate,
`
`thioglycolic acid,
`
`EDTA, pentetate, sodium metabisulfite, and others known to those of ordinary skill in the
`
`art.
`
`As used herein, the term “buffering agent” is intended to mean a compound used to
`
`resist change in pH upon dilution or addition of acid or alkali. Buffers are used in the
`
`present compositions to adjust the pH to a range of between about 2 and about 8, about 3
`
`to about 7, or about 4 to about 5. Such compounds include, by way of example and
`
`without limitation, acetic acid, sodium acetate, adipic acid, benzoic acid, sodium benzoate,
`
`boric acid, sodium borate, citric acid, glycine, maleic acid, monobasic sodium phosphate,
`
`dibasic sodium phosphate, HEPES, lactic acid, tartaric acid, potassium metaphosphate,
`
`potassium phosphate, monobasic sodium acetate, sodium bicarbonate, tris, sodium tartrate
`
`and sodium citrate anhydrous and dihydrate and others known to those of ordinary skill in
`
`the art. Other buffers include citric acid/phosphate mixture, acetate, barbital, borate,
`
`Britton—Robinson, cacodylate, citrate, collidine, formate, maleate, Mcllvaine, phosphate,
`
`Prideaux—Ward, succinate, citrate—phosphate—borate (Teorell—Stanhagen), veronal acetate,
`
`MES (2—(N—morpholino)ethanesulfonic
`
`acid), BIS—TRIS
`
`(bis(2—hydroxyethyl)imino—
`
`tris(hydroxymethyl)methane), ADA (N—(2—acetamido)—2—iminodiacetic acid), ACES (N—
`
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`(carbamoylmethyl)—2-aminoethanesulfonaic
`
`acid),
`
`PIPES
`
`(piperazine-N,N'-bis(2-
`
`ethanesulfonic acid)), MOPSO (3—(N—morpholino)—2—hydroxypropanesulfonic acid), BIS—
`
`TRIS PROPANE (1,3—bis(tris(hydroxymethyl)methylamino)propane), BES (N,N—bis(2—
`
`hydroxyethyl)—2—aminoethancsulfonaic acid), MOPS (3—(N—morpholino)propancsulfonic
`
`acid), TES (N—tris(hydroxymethyl)methyl—2—aminoethanesulfonic acid), IIEPES (N—(2—
`
`hydroxyethyl)piperazine—N'—(2—ethanesulfonic
`
`acid),
`
`DIPSO
`
`(3—(N,N—bis(2—
`
`hydroxyethyl)amino)—2—hydroxypropanesulfonic
`
`acid), MOBS
`
`(4—(N—morpholino)—
`
`butanesulfonic
`
`acid),
`
`TAPSO
`
`(3—(N—tris(hydroxymethyl)methylamino)—2—
`
`hydroxypropanesulfonic acid), TRIZMATM (tris(hydroxymethylaminomethane), HEPPSO
`
`(N—(2-hydroxyethyl)piperazine-N'-(2-hydroxypropanesulfonic acid), POPSO (piperazine-
`
`N,N'—bis(2—hydroxypropanesulfonic
`
`acid)), TEA (triethanolamine),
`
`EPPS
`
`(N—(2—
`
`hydroxyethyl)piperazine—N'—(3—propanesulfonic
`
`acid),
`
`TRICINE
`
`(N—
`
`tris(hydroxymcthyl)methylglycinc), GLY—GLY (glycylglycinc), BICINE (N,N—bis(2—
`
`hydroxyethyl) glycine),
`
`IIEPBS
`
`(N— (2—hydroxyethyl)piperazine—N'—(4—butanesulfonic
`
`acid)), TAPS (N—tris(hydroxymethyl)methyl—3—aminopropanesulfonic acid), AMPD (2—
`
`amino—2—methyl—1,3—propanediol), and/or any other buffers known to those of skill in the
`
`art.
`
`A complexation—enhancing agent can be added to the compositions of the
`
`invention. When such an agent is present, the ratio of cyclodeXtrin /active agent can be
`
`changed. A complexation—enhancing agent is a compound, or compounds, that enhance(s)
`
`the complexation of the active agent with the cyclodextrin.
`
`Suitable complexation
`
`enhancing agents include one or more pharmacologically inert water soluble polymers,
`
`hydroxy acids, and other organic compounds typically used in liquid formulations to
`
`enhance the complexation of a particular agent With cyclodextrins.
`
`Hydrophilic polymers
`
`can be used as
`
`complexation—enhancing,
`
`solubility—
`
`enhancing and/or water activity reducing agents
`
`to improve the performance of
`
`formulations containing a cyclodeXtrin. Suitable polymers are disclosed in Pharmazie
`
`(2001), 56(9), 746—747; International Journal of Pharmaceutics (2001), 212(1), 29—40;
`
`Cyclodextrin: From Basic Research to Market, International Cyclodextrin Symposium,
`
`10th, Ann Arbor, MI, United States, May 21—24, 2000 (2000), 10—15 (Wacker Biochem
`
`Corp: Adrian, Mich.); PCT International Publication No. W() 9942111; Pharmazic,
`
`53(11), 733—740 (1998); Pharm. Technol. Eur, 9(5), 26—34 (1997); J. Pharm. Sci. 85(10),
`
`1017—1025
`
`(1996); European Patent Application EP0579435; Proceedings of
`
`the
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`International Symposium on CyclodeXtrins, 9th, Santiago de Comostela, Spain, May 31-
`
`June 3, 1998 (1999), 261—264 (Editor(s): Labandeira, J. J. Torres; Vila—Jato, J. L. Kluwer
`
`Academic Publishers, Dordrecht, Neth); S.T.P. Pharma Sciences (1999), 9(3), 237—242;
`
`ACS Symposium Series (1999), 737(Polysaccharidc Applications), 24—45; Pharmaceutical
`
`Research (1998), 15(11), 1696—1701; Drug Development and Industrial Pharmacy (1998),
`
`24(4), 365—370; International Journal ofPharmaceutics (1998), 163(1—2), 115—121; Book
`
`of Abstracts, 216th ACS National Meeting, Boston, August 23—27 (1998), CELL—016,
`
`American Chemical Society; Journal of Controlled Release,
`
`(1997), 44/1 (95—99);
`
`Pharm.Res. (1997) 14(11), S203; Investigative Ophthalmology & Visual Science, (1996),
`
`37(6), 1199-1203; Proceedings of the International Symposium on Controlled Release of
`
`Bioactive Materials (1996), 23rd, 453—454; Drug Development and Industrial Pharmacy
`
`(1996), 22(5), 401—405; Proceedings of the International Symposium on Cyclodextrins,
`
`8th, Budapest, Mar. 31—Apr. 2, (1996), 373—376.
`
`(Editor(s): Szcjtli, J.; Szcntc, L. Kluwcr:
`
`Dordrecht, Neth.); Pharmaceutical Sciences (1996), 2(6), 277—279; European Journal of
`
`Pharmaceutical Sciences,
`
`(1996) 4(SUPPL.), S144; Third European Congress of
`
`Pharmaceutical Sciences Edinburgh, Scotland, UK September 15—17, 1996; Pharmazie,
`
`(1996), 51(1), 39—42; Eur. J. Pharm. Sci.
`
`(1996), 4(Suppl.), S143; US. Patents No.
`
`5,472,954 and No. 5,324,718; International Journal of Pharmaceutics (Netherlands),
`
`(Dec. 29, 1995) 126, 73—78; Abstracts of Papers of the American Chemical Society, (02
`
`APR 1995) 209(1), 33—CELL; European Journal of Pharmaceutical Sciences, (1994) 2,
`
`297—301; Pharmaceutical Research (New York),
`
`(1994) 11(10), 8225; International
`
`Journal of Pharmaceutics (Netherlands), (Apr 11, 1994) 104, 181—184; and International
`
`Journal of Pharmaceutics (1994), 110(2), 169—77, the entire disclosures of which are
`
`hereby incorporated by reference.
`
`Other suitable polymers are well—known excipients commonly used in the field of
`
`pharmaceutical
`
`formulations
`
`and
`
`are
`
`included
`
`in,
`
`for
`
`example, Remington 's
`
`Pharmaceutical Sciences, 18th Edition, Alfonso R. Gennaro (editor), Mack Publishing
`
`Company, Easton, PA, 1990, pp. 291—294; Alfred Martin, James Swarbrick and Arthur
`
`Commarata, Physical Pharmacy. Physical Chemical Principles
`
`in Pharmaceutical
`
`Sciences, 3rd edition (Lea & Febinger, Philadelphia, PA, 1983, pp. 592—638); A.T.
`
`Florence and D. Altwood,
`
`(Physicochemical Principles of Pharmacy, 2nd Edition,
`
`MacMillan Press, London, 1988, pp. 281—334. The entire disclosures of the references
`
`cited herein are hereby incorporated by references. Still other suitable polymers include
`
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`water-soluble natural polymers, water—soluble semi-synthetic polymers (such as the water-
`
`soluble derivatives of cellulose) and water—soluble synthetic polymers. The natural
`
`polymers include polysaccharides such as inulin, pectin, algin derivatives (e. g. sodium
`
`alginate) and agar, and polypeptides such as casein and gelatin. The semi—synthetic
`
`polymers include cellulose derivatives such as methylcellulose, hydroxyethylcellulose,
`
`hydroxypropyl cellulose, their mixed ethers such as hydroxypropyl methylcellulose and
`
`other mixed ethers such as hydroxyethyl ethylcellulose and hydroxypropyl ethylcellulose,
`
`hydroxypropyl methylcellulose phthalate and carboxymethylcellulose and its
`
`salts,
`
`especially
`
`sodium carboxyrnethylcellulose.
`
`The
`
`synthetic
`
`polymers
`
`include
`
`10
`
`polyoxyethylene derivatives (polyethylene glycols) and polyvinyl derivatives (polyvinyl
`
`alcohol, polyvinylpyrrolidone and polystyrene sulfonate) and various copolymers of
`
`acrylic acid (e.g. carbomer). Other natural, semi—synthetic and synthetic polymers not
`
`named here which meet the criteria of water solubility, pharmaceutical acceptability and
`
`pharmacological inactivity are likewise considered to be within the ambit of the present
`
`15
`
`invention.
`
`An emulsifying agent is intended to mean a compound that aids the formation of
`
`an emulsion. An emulsifier can be used to wet the corticorsteroid and make it more
`
`amenable to dissolution. Emulsifiers for use herein include, but are not limited to,
`
`polyoxyetheylene sorbitan fatty esters or polysorbates,
`
`including, but not
`
`limited to,
`
`polyethylene sorbitan monooleate (Polysorbate 80), polysorbate 20 (polyoxyethylene (20)
`
`sorbitan monolaurate), polysorbate 65
`
`(polyoxyethylene (20)
`
`sorbitan tristearate),
`
`polyoxyethylene (20) sorbitan mono—oleate, polyoxyethylene (20) sorbitan monopalmitate,
`
`polyoxyethylene (20) sorbitan monostearate;
`
`lecithins; alginic acid; sodium alginate;
`
`potassium alginate; ammonium alginate; calcium alginate; propane—1,2—diol alginate; agar;
`
`carrageenan; locust bean gum; guar gum; tragacanth; acacia; xanthan gum; karaya gum;
`
`pectin;
`
`amidated
`
`pectin;
`
`ammonium phosphatides; microcrystalline
`
`cellulose;
`
`methylcellulose;
`
`hydroxypropylcellulose;
`
`hydroxypropylmethylcellulose;
`
`ethylmethylcellulose; carboxymethylcellulose; sodium, potassium and calcium salts of
`
`fatty acids; mono—and di—glycerides of fatty acids; acetic acid esters of mono— and di—
`
`glycerides of fatty acids; lactic acid esters of mono—and di—glycerides of fatty acids; citric
`
`acid esters of mono—and di—glycerides of fatty acids; tartaric acid esters of mono—and di—
`
`glycerides of fatty acids; mono—and diacetyltartaric acid esters of mono—and di—glycerides
`
`of fatty acids; mixed acetic and tartaric acid esters of mono—and di—glycerides of fatty
`
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`acids; sucrose esters of fatty acids; sucroglycerides; polyglycerol esters of fatty acids;
`
`polyglycerol esters of polycondensed fatty acids of castor oil; propane—1,2—diol esters of
`
`fatty acids; sodium stearoyl—Z—lactylate; calcium stearoyl—Z—lactylate; stearoyl
`
`tartrate;
`
`sorbitan monostcaratc; sorbitan tristcaratc; sorbitan monolauratc; sorbitan monoolcatc;
`
`sorbitan monopalmitate; extract of quillaia; polyglycerol esters of dimerised fatty acids of
`
`soya bean oil; oxidatiVely polymerised soya bean oil; and pectin extract.
`
`As used herein, the term “stabilizer” is intended to mean a compound used to
`
`stabilize the therapeutic agent against physical, chemical, or biochemical process that
`
`would reduce the therapeutic actiVity of the agent. Suitable stabilizers include, by way of
`
`example and without limitation, albumin, sialic acid, creatinine, glycine and other amino
`
`acids, niacinamide, sodium acetyltryptophonate, zinc oxide, sucrose, glucose,
`
`lactose,
`
`sorbitol, mannitol, glycerol, polyethylene glycols, sodium caprylate, sodium saccharin and
`
`other known to those of ordinary skill in the art.
`
`As used herein, the term “Viscosity modifier” is intended to mean a compound or
`
`mixture of compounds that can be used to adjust the Viscosity of an aqueous liquid
`
`composition of the invention.
`
`The Viscosity modifier can increase or decrease the
`
`Viscosity.
`
`Suitable Viscosity modifiers
`
`include HPMC,
`
`CMC
`
`(sodium
`
`carboxymethylcellulose), glycerin, PEG and others recognized by artisans in the field.
`
`In
`
`some embodiments, the composition excludes HPMC.
`
`As used herein, the term “tonicity modifier” is intended to mean a compound or
`
`compounds that can be used to adjust the tonicity of the liquid formulation. Suitable
`
`tonicity modifiers include glycerin, lactose, mannitol, dextrose, sodium chloride, sodium
`
`sulfate, sorbitol, trehalose and others known to those of ordinary skill in the art. Other
`
`tonicity modifiers include both inorganic and organic tonicity adjusting agents. Tonicity
`
`modifiers include, but are not limited to, ammonium carbonate, ammonium chloride,
`
`ammonium lactate, ammonium nitrate, ammonium phosphate, ammonium sulfate,
`
`ascorbic acid, bismuth sodium tartrate, boric acid, calcium chloride, calcium disodium
`
`edetate, calcium gluconate, calcium lactate, citric acid, dextrose, diethanolamine,
`
`dimethylsulfoxide, edetate disodium, edetate trisodium monohydrate, fluorescein sodium,
`
`fructose, galactose, glycerin, lactic acid, lactose, magnesium chloride, magnesium sulfate,
`
`mannitol, polyethylene glycol, potassium acetate, potassium chlorate, potassium chloride,
`
`potassium iodide, potassium nitrate, potassium phosphate, potassium sulfate, proplyene
`
`glycol, silver nitrate, sodium acetate, sodium bicarbonate, sodium biphosphate, sodium
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`bisulfite, sodium borate, sodium bromide, sodium cacodylate, sodium carbonate, sodium
`
`chloride, sodium citrate, sodium iodide, sodium lactate, sodium metabisulfite, sodium
`
`nitrate, sodium nitrite, sodium phosphate, sodium propionate, sodium succinate, sodium
`
`sulfate, sodium sulfite, sodium tartrate, sodium thiosulfatc, sorbitol, sucrose, tartaric acid,
`
`triethanolamine, urea, urethan, uridine and zinc sulfate.
`
`In some embodiments,
`
`the
`
`tonicity of the liquid formulation approximates the tonicity of the tissues in the respiratory
`
`tract.
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`15
`
`An osmotic agent can be used in the compositions to enhance the overall comfort
`
`to the patient upon delivery of the corticosteroid composition. Osmotic agents can be
`
`added to adjust the tonicity of SAE—CD containing solutions. Osmolality is related to
`
`concentration of SAE—CD in water. At SBE7—B—CD concentrations below about 11—13%
`
`w/v, the solutions are hypotonic or hypoosmotic with respect to blood and at SBE7—l3—CD
`
`concentrations above about
`
`11—13% w/v the SBE7—B—CD containing solutions are
`
`hypertonic or hyperosmotic with respect to blood. When red blood cells are exposed to
`
`solutions that are hypo— or hypertonic, they can shrink or swell in size, which can lead to
`
`hemolysis.
`
`SBE—CD is
`
`less prone to induce hemolysis
`
`than other derivatized
`
`cyclodextrins. Suitable osmotic agents include any low molecular weight water—soluble
`
`species pharmaceutically approved for nasal delivery such as sodium chloride, lactose and
`
`glucose. The formulation of the invention can also include biological salt(s), potassium
`
`20
`
`chloride, or other electrolyte(s).
`
`As used herein, the term “antifoaming agent” is intended to mean a compound or
`
`compounds that prevents or reduces the amount of foaming that forms on the surface of
`
`the liquid formulation. Suitable antifoaming agents include dimethicone, simethicone,
`
`octoxynol, ethanol and others known to those of ordinary skill in the art.
`
`25
`
`As used herein, the term “bulking agent” is intended to mean a compound used to
`
`add bulk to the lyophilized product and/or assist in the control of the properties of the
`
`formulation during lyophilization. Such compounds include, by way of example and
`
`without limitation, dextran,
`
`trehalose, sucrose, polyvinylpyrrolidone,
`
`lactose,
`
`inositol,
`
`sorbitol, dimethylsulfoxide, glycerol, albumin, calcium lactobionate, and others known to
`
`30
`
`those of ordinary skill in the art.
`
`A solubility—enhancing agent or
`
`solubility enhancer can be added to the
`
`formulation of the invention. A solubility—enhancing agent is a compound, or compounds,
`
`that enhance(s) the solubility of the corticosteroid when in an aqueous liquid carrier.
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`When another solubility enhancing agent is present, the ratio of SAE—CD to corticosteroid
`
`can be changed,
`
`thereby reducing the amount of SAE—CD required to dissolve the
`
`corticosteroid. Suitable solubility enhancing agents include one or more cyclodextrins,
`
`cyclodcxtrin derivatives, SAE—CD, organic solvents, dctcrgcnts, soaps, surfactant and
`
`other organic compounds typically used in parenteral
`
`formulations to enhance the
`
`solubility of a particular agent. Exemplary solubility enhancers are disclosed in US.
`
`Patent No. 6,451,339; however, other surfactants used in the pharmaceutical industry can
`
`be used in the formulation of the invention.
`
`Some suitable cyclodextrin include
`
`underivatized cyclodextrins and cyclodextrin derivatives, such as SAE-CD, SAE-CD
`
`derivatives, hydroxyalkyl ether cyclodextrin and derivatives, alkyl ether cyclodextrin and
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`derivatives, sulfatcd cyclodcxtrin and derivatives, hydroxypropyl—B—cyclodcxtrin, 2—HP—B—
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`CD, methyl—B—cyclodextrin, carboxyalkyl thioether derivatives, succinyl cyclodextrin and
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`derivatives,
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`and other
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`cyclodextrin suitable
`
`for pharmaceutical use.
`
`SAE-CD
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`cyclodextrins are particularly advantageous.
`
`Suitable surfactants
`
`include phospholipids, among other compounds, which
`
`include for example phosphocholines or phosphatidylcholines, in which the phosphate
`
`group is additionally esterified with choline, furthermore phosphatidyl ethanolamines,
`
`phosphatidyl inositols, lecithins. Other ionic surfactants which can seive as solubility—
`
`enhancing agents are, for example, sodium lauryl sulfate, sodium cetylstearyl sulfate,
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`sodium (or calcium or potassium) docusate, medium and long chain fatty acids.
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`SAE—CD can serve as a taste—masking agent by complexation with poor—tasting
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`molecule. For example, SAE—CD can complex with a bitter or sour tasting active agent in
`
`a composition of the invention to reduce the bittemess or sourness of the agent as
`
`compared to the uncomplexed active agent. Accordingly, “improved taste” or “taste—
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`masking” is taken to mean a reduction in the bitterness or sourness of a composition or
`
`active agent. Active agents can differ in the native bitterness or sourness. For example,
`
`olopatadine is known to have reduced bitterness as compared to azelastine. The invention
`
`includes taste—masked embodiments, wherein the SAE—CD is complexed with an active
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`agent having reduced bitterness or reduced sourness as compared to another active agent.
`
`In some embodiments, the methods, systems, devices, and compositions of the
`
`invention are associated with improved taste of a therapeutic agent as compared to the
`
`therapeutic agent alone or in existing formulations.
`
`In some embodiments, the improved
`
`taste is associated with administration of an antihistamine.
`
`In some embodiments, the
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`improved taste is associated with administration of azelastine. The effectiveness of SAE-
`
`CD at masking the taste of a drug can be determined, for example, according to Example
`
`31, which details the procedure used to conduct an electronic tongue study on a
`
`composition comprising SBE—B—CD and azelastine.
`
`If desired, the composition further comprises an aqueous liquid carrier other than
`
`water. Suitable organic solvents that can be used in the formulation include, for example,
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`ethanol, glycerin, poly(ethylene glycol), propylene glycol, poloxamer, aqueous forms
`
`thereof, others known to those of ordinary skill in the art and combinations thereof.
`
`It should be understood that compounds used in the art of pharmaceutical
`
`formulations gcncrally serve a variety of functions or purposes. Thus, if a compound
`
`named herein is mentioned only once or is used to define more than one term herein, its
`
`purpose or function should not be construed as being limited solely to that named
`
`purpose(s) or function(s).
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`A composition can be purged with an inert gas prior to storage to remove
`
`substantially all of the oxygen contained in the formulation.
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`In general, the formulation or
`
`composition of the invention has a shelf—life of at least 6 months depending upon the
`
`intended use.
`
`If needed, the SAE—CD—containing formulation can be prepared as a clear aqueous
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`solution that can be sterile filtered through a filter having a pore size of 0.45 pm or less
`
`and that is stable and preserved under a variety of storage conditions. The invention thus
`
`provides a filtration-sterilized liquid formulation comprising a solution of the invention
`
`and a method of sterilizing a solution of the invention by sterile filtration through a filter.
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`Sterile filtration can be done without substantial mass loss of solubilized corticosteroid,
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`meaning less than 5% mass loss.
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`The formulation can be prepared at a temperature at or above 5°C, at or above
`
`25°C, at or above 35°C, at or above 45°C or at or above 50°C. Specific embodiments of
`
`the methods of preparing a liquid formulation include those wherein:
`
`l) the method
`
`further comprises sterile filtering the formulation through a filtration medium having a
`
`pore size of 0.1 microns or larger; 2) the liquid formulation is sterilized by irradiation or
`
`autoclaving; and/or 3) the nebulization solution is purged with nitrogen or argon or other
`
`inert pharmaceutically acceptable gas prior to storage such that a substantial portion of the
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`oxygen dissolved in, and/or in surface contact with the solution is removed.
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`An active agent contained within the present formulation can be present as its
`
`pharmaceutically acceptable salt. As used herein, “pharmaceutically acceptable salt”
`
`refers to derivatives of the disclosed compounds wherein the active agent is modified by
`
`reacting it with an acid or base as needed to form an ionically bound pair. Examples of
`
`pharmaceutically acceptable salts include conventional non—toxic salts or the quaternary
`
`ammonium salts of the parent compound formed, for example, from non—toxic inorganic
`
`or organic acids. Suitable non—toxic salts include those derived from inorganic acids such
`
`as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and others
`
`known to those of ordinary skill in the art. The salts prepared from organic acids such as
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`amino acids, acetic, propionic, succinic, glycolic, stearic,
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`lactic, malic,
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`tartaric, citric,
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`ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,
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`sulfanilic, Z—acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic,
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`oxalic,
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`iscthionic, and others known to those of ordinary skill
`
`in the art.
`
`The
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`pharmaceutically acceptable salts of the present invention can be synthesized from the
`
`parent active agent which contains a basic or acidic moiety by conventional chemical
`
`methods. Lists of other suitable salts are found in Remington ’s Pharmaceutical Sciences,
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`17th. ed., Mack Publishing Company, Easton, PA, 2005, the relevant disclosure of which is
`
`hereby incorporated by reference.
`
`The phrase “pharmaceutically acceptable” is employed herein to refer to those
`
`compounds, materials, compositions, and/or dosage forms which are, within the scope of
`
`sound medical judgment, suitable for use in contact with the tissues of human beings and
`
`animals without excessive toxicity,
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`irritation, allergic response, or other problem or
`
`complication, commensurate with a reasonable benefit/risk ratio.
`
`As used herein, the term “patient” or “subject” are taken to mean humans and non—
`
`humans, such as mammals, for example, cats, dogs, mice, guinea pigs, horses, bovine
`
`cows, and sheep.
`
`The utility and therapeutic efficacy of a nasal aqueous liquid composition
`
`according
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`to
`
`the
`
`invention
`
`for
`
`the
`
`treatment
`
`of
`
`seasonal
`
`allergic
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`rhinitis
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`(SAR)/conjunctivitis (SARC) was demonstrated in a clinical trial conducted according to
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`Example 33.
`
`The time to target or peak therapeutic effect
`
`is
`
`the period of time after
`
`administration of a dose that it takes for the active agent to achieve the target or peak
`
`therapeutic effect, respectively, in a subject. The onset of a target or desired therapeutic
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`effect is the point in time that the beginning of the target or desired therapeutic effect is
`
`first observed in the subject after administration of a composition.
`
`In some embodiments, the compositions, methods, and systems of the invention
`
`rclicvc non—nasal symptoms sooner and to a greater degree than an aqueous suspension—
`
`based formulation comprising the same unit dose of corticosteroid and administered under
`
`substantially the same conditions but excluding SAE—CD.
`
`In some embodiments, the
`
`compositions and systems provide more rapid relief of nasal symptoms than the aqueous
`
`suspension based formulation. The compositions and systems of the invention also
`
`provide simplified manufacture, improved administered—dose uniformity, and improved
`
`taste-masking and odor—masking
`
`as
`
`compared to
`
`the
`
`aqueous
`
`suspension-based
`
`formulation.
`
`In some embodiments,
`
`the compositions, methods, and systems of the
`
`invention provide an enhanced and/or more rapid onset of a target or desired therapeutic
`
`effect and/or a more rapid time to target, desired or peak therapeutic effect as compared to
`
`the aqueous suspension—based compositions, methods, or systems excluding SAE—CD.
`
`A therapeutic effect will be observed following administration of a composition.
`
`The onset of a target or desired therapeutic effect is the point in time that the beginning of
`
`the target or desired therapeutic effect is first observed in the subject after administration
`
`of a composition.
`
`In some embodiments, the onset of a target or desired therapeutic effect
`
`generally occurs within 0.1 min to 120 min, 1 min to 90 min, 1 min to 60 min, 1 min to 30
`
`min,
`
`1 min to 20 min,
`
`1 min to 15 min, or 1 min to 10 min after nasal or ophthalmic
`
`administration of the composition.
`
`In some embodiments, the time to a target or peak therapeutic effect can occur
`
`from minutes to hours after administration.
`
`In some embodiments, the time to can occur
`
`from 8 to 10 hours, within 1 to 2 days, or within 1 to 2 weeks after nasal or ophthalmic
`
`administration of the composition, said administration being conducted according to a
`
`dosing regimen as detailed herein.
`
`In some embodiments, the methods, systems, devices, and compositions of the
`
`invention comprise a combination of corticosteroid and azelastine with SAE—CD in a
`
`solution that
`
`is useful for treating nasal, non—nasal, and ocular symptoms. In some
`
`embodiments, the symptoms are allergic symptoms resulting from exposure of a subject to
`
`an airborne allergen.
`
`A clinical study according to Example 34 was conducted to demonstrate the
`
`therapeutic
`
`efficacy of
`
`a nasal
`
`composition comprising budesonide,
`
`azelastine
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`hydrochloride, CAPTISOL and buffer as compared to the sequential administration of
`
`RHINOCORT AQUA (RA) and ASTELIN (AST).
`
`In some embodiments,
`
`the nasal compositions, systems, and methods of the
`
`invention comprising a corticosteroid, SAE—CD and an antihistamine provides
`
`a
`
`therapeutic effect (clinical benefit) that approximates or is enhanced over the therapeutic
`
`effect provided by the separate and sequential nasal administration of: a) an aqueous
`
`suspension composition comprising the same unit dose of corticosteroid; and b) an
`
`aqueous composition comprising the same unit dose of antihistamine.
`
`In some
`
`embodiments,
`
`the therapeutic effect
`
`is relief of nasal, non-nasal and ocular allergic
`
`symptoms.
`
`In some embodiments,
`
`the nasal composition, system and method of the
`
`invention provide an improved quality of life in subjects suffering from an allergic
`
`disorder, such as SAR and/or SARC.
`
`The compositions, methods, and systems of the invention can provide an enhanced
`
`therapeutic
`
`effect
`
`as
`
`compared to
`
`a
`
`suspension—based
`
`aqueous
`
`formulation of
`
`corticosteroid. The enhanced therap