US 20060045850A1 (19) United States (12) Patent Application Publication (10) Pub. N0.: US 2006/0045850 A1 Namburi et al. (43) Pub. Date: Mar. 2, 2006

(54) NASAL DELIVERY OF CYCLODEXTRIN Publication Classi?cation COMPLEXES OF ANTI-INFLAMMATORY (51) Int. Cl. A61K 31/724 (2006.01) A61K 9/14 (2006.01) A61L 9/04 (2006.01) (75) Inventors: Ranga R. Namburi, Plainsboro, NJ (52) Us. 01...... 424/46; 514/58 (US); Sucharitha Jagini, Edison, NJ (US); Burgise F. Palkhiwala, East (57) ABSTRACT Windsor, NJ (US) Aqueous, anti-in?ammatory compositions in solu tion form suitable for nasal administration and having a reduced stinging sensation are provided as Well as a method Correspondence Address: for treating in?ammation of the nasal mucosa by intranasal Richard S. Roberts administration of anti-in?ammatory steroid compositions. These solution compositions may result in enhanced nasal PO. Box 484 bio-availability. The anti-in?ammatory steroid composition Princeton, NJ 08542-0484 (US) suitable for intranasal administration includes an anti-in ?ammatory steroid in an amount of from about 0.0001% to about 2.0% (W/v); a cyclodextrin in an amount of from about (73) Assignee: QPharma, LLC 0.1% to about 20% (W/v); an alcohol co-solvent in an amount of from about 0.2% to about 35% (W/v); a crystal lization inhibitor Where required, an effective amount of an (21) Appl. No.: 10/930,986 antimicrobial preservative; an effective amount of an anti oxidant; an effective amount of a chelating agent; Water; and a pH adjusting agent sufficient to adjust the pH of the (22) Filed: Aug. 30, 2004 composition to from about 4 to about 7. US 2006/0045850 A1 Mar. 2, 2006

NASAL DELIVERY OF CYCLODEXTRIN lation for use in female contraception and the composition is COMPLEXES OF ANTI-INFLAMMATORY comprised of a GnRH compound and an estrogenic com STEROIDS pound in the form of Water soluble complex With a Water soluble cyclodextrin. The method used to combine cyclo BACKGROUND OF THE INVENTION dextrins and hormones in these patents is different from this invention. US. Pat. No. 5,089,482 combines cyclodextrin [0001] 1. Field of the Invention With the hormones through using a solvent and removing the [0002] The present invention pertains to aqueous solution, solvent through evaporation process and the complex that is anti-in?ammatory steroid compositions suitable for nasal formed in this process is combined With other formulation administration. The invention also pertains to a method for excipients. Thus there is a need for formation of a clear treating in?ammation of the nasal mucosa by intranasal solution formulation of the steroids using simple and indus administration of anti-in?ammatory steroid compositions. trially feasible appropriate methods. The compositions of More particularly, the invention pertains to stable anti the present invention are stable, preservable, and are suitable in?ammatory steroid compositions for intranasal adminis for nasal administration of anti-in?ammatory steroids and tration having a reduced stinging sensation. The invention have a reduced stinging tendency. In this invention a mini formulations in solution form may result in enhanced bio mum amount of co-solvent (adjuvant) is used to dissolve the availability from the nose. active steroid With application of heat and it is then com bined With aqueous phase containing cyclodextrin. The [0003] 2. Description of the Related Art invention also proves that cyclodextrin forms a complex [0004] Anti-in?ammatory steroid compositions suitable With the active and remains in solution in spite of the fact for nasal administration are knoWn in the art. Typically these that loW percentage of cosolvent is used in the formulation. include a cortical steroid such as ?unisolide, beclometha The invention formulations of beclomethasone dipropionate sone dipropionate, budenoside, furoate or ?u and ?uticasone propionate teach the addition of a crystalli ticasone propionate. Anti-in?ammatory steroids are di?icult Zation inhibitor, such as hydroxy propyl methyl cellulose, in to formulate in aqueous solutions due to their poor solubility the formulation to prevent precipitation upon storage in vieW in Water. Acceptable formulations must be able to dissolve of their extremely loW solubility in Water and also their an active compound Without precipitation or suspend the molecular siZe. The solubility and stability of beclometha active Without agglomeration or particle siZe increase upon sone and ?uticasone is increased in presence of crystalliZa storage or undue oxidation of the components, i.e. they must tion inhibitor such as hydroxyl propyl methyl cellulose. be stable. Suitable formulations must also avoid discomfort to the user. Aqueous compositions of anti-in?ammatory SUMMARY OF THE INVENTION steroids such as ?unisolide suitable for nasal administration [0006] The invention provides an anti-in?ammatory ste are commercially available, for example under the trade roid composition suitable for intranasal administration marks Nasalide® and Nasarel®. HoWever, currently avail Which comprises: able compositions, While safe and effective, are knoWn to cause stinging upon administration in some cases. Such a [0007] an anti-in?ammatory steroid in an amount of side effect is particularly undesirable When treating nasal from about 0.0001% to about 2.0% (W/v); in?ammation. Adjuvants such as propylene glycol in higher concentration (more than 10 percent), Polysorbate 80 or [0008] a cyclodextrin in an amount of from about 0.1% to about 20% (W/v); TWeen 80 suitable for use as solubiliZers, hoWever, are often unsuitable for the nasal mucosa and/or have an insu?icient [0009] an alcohol co-solvent in an amount of from solubility. A chronic therapy With such a composition is about 0.2% to about 35% (W/v); undesirable. [0010] an effective amount of an antimicrobial preser [0005] Nasonex® (Mometasone Furoate), Beconase AQ® vative; (Beclomethasone Dipropionate), Nasacort AQ®A (Triamci nolone Acetonide), Rhinocort® Aqua (Budenoside) and [0011] 1an effective amount of an antioxidant; Flonase® ( Propionate) are marketed formula [0012] 1an effective amount of a chelating agent; tions With actives suspended. Absolute bio-availability of these suspension formulations is loW and for example the [0013] Water; and absolute bio-availability of Fluticasone from the suspension formulation When administered nasally is less than 2.0 [0014] a pH adjusting agent su?icient to adjust the pH percent and it has no absorption When administered orally. of the composition to from about 4 to about 7. Hence, there is a clear need for development of clear [0015] The composition may also contain a crystalliZation solution formulations of the steroids. US. Pat. No. 6,241, inhibitor in an amount of from about 0.01% to 10% W/V. 969 provides aqueous compositions containing corticoster oids for nasal and pulmonary delivery Which comprises at [0016] The invention also provides a method of treating least 50% by Weight of an ethoxylated derivative of vitamin in?ammation of the nasal mucosa, Which method comprises E. US. Pat. Nos. 4,782,047 and 4,983,595 shoW an aqueous intranasally administering to a subject in need thereof an steroid formulation for nasal administration, hoWever, no anti-in?ammatory steroid composition comprising: cyclodextrins are taught. US. Pat. Nos. 5,089,482, 5,955, [0017] an anti-in?ammatory steroid in an amount of 454 and WO 00/21503 shoW aqueous formulations of hor from about 0.0001% to about 2.0% (W/v); mones for nasal administration using cyclodextrins, hoW ever, no are shoWn. US. patent application [0018] a cyclodextrin in an amount of from about 0.1% 2004022739 also teaches preparation of nasal spray formu to about 20% (W/v); US 2006/0045850 A1 Mar. 2, 2006

[0019] an alcohol co-solvent in an amount of from most useful pharmaceutical complexing agent due to its about .2% to about 35% (W/v); cavity siZe, availability, loW cost and other properties. Cyclodextrin derivatives of current pharmaceutical interest [0020] an effective amount of an antimicrobial preser include the hydroxypropyl derivatives of ot-, [3- and y-cy vat1ve; clodextrin, sulfoalkylether cyclodextrins such as sulfobu [0021] an effective amount of an antioxidant; tylether [3-cyclodextrin, alkylated cyclodextrins such as the randomly methylated [3-cyclodextrin, and various branched [0022] an effective amount of a chelating agent; cyclodextrins such as glucosyl- and maltosyl [3-cyclodextrin. [0023] Water; and [0029] In aqueous solutions, cyclodextrins form inclusion [0024] a pH adjusting agent suf?cient to adjust the pH complexes With many drugs through a process in Which the of the composition to from about 4 to about 7. Water molecules located in the central cavity are replaced by either the Whole drug molecule, or more frequently, by some [0025] The composition may also contain a crystallization lipophilic portion of the drug structure. Once included in the inhibitor in an amount of from about 0.01% to 10% W/V. cyclodextrin cavity, the drug molecules may be dissociated [0026] Commercially available metered dose pumps and through complex dilution, by replacement of the included bottles are used for ?lling of the invention formulations. drug by some other suitable molecule or, the drug may be transferred to the matrix for Which it has the highest affinity. DETAILED DESCRIPTION OF THE Importantly, since no covalent bonds are formed or broken INVENTION during the drug-cyclodextrin complex formation, the com plexes are in dynamic equilibrium With free drug and [0027] The composition of the invention includes an anti cyclodextrin molecules. In solution, the complexes are usu in?ammatory steroid, such as a . The corticos ally prepared by addition of an excess amount of the drug to teroids that are useful in the present invention generally an aqueous cyclodextrin solution. The suspension formed is include any steroid produced by the adrenocortex, including and then ?ltered or centrifuged to form a clear drug and mineralocorticoids, and synthetic ana cyclodextrin complex solution. logs and derivatives of naturally occurring corticosteroids [0030] Useful cyclodextrins for use in the present inven having anti-in?ammatory activity. Examples of corticoster tion non-exclusively include alkyl cyclodextrins, hydroxy oids that can be used in the compositions of the invention alkyl cyclodextrin, such as hydroxy propyl [3-cyclodextrin, include aldosterone, beclomethasone, , carboxy alkyl cyclodextrins and sulfoalkyl ether cyclodex , , , , deoxycortone, trin, such as sulfo butyl ether [3-cyclodextrin. Examples of , , , di?uorocor suitable cyclodextrins for use in the present invention non tolone, ?uclorolone, ?umethasone, ?unisolide, ?uocinolone, exclusively include ot-cyclodextrin; [3-cyclodextrin; y-cyclo ?uocinonide, ?uocortin butyl, ?uorocortisone, ?uorocor dextrin; methyl ot-cyclodextrin; methyl [3-cyclodextrin; tolone, ?uorometholone, ?urandrenolone, ?uticasone, ?uti methyl y-cyclodextrin; ethyl [3-cyclodextrin; butyl ot-cyclo casone propionate, , , icometha dextrin; butyl [3-cyclodextrin; butyl y-cyclodextrin; pentyl sone, , , mometasone y-cyclodextrin; hydroxyethyl [3-cyclodextrin; hydroxyethyl , mometasone furoate monohydrate, pred y-cyclodextrin; 2-hydroxypropyl ot-cyclodextrin; 2-hydrox nisolone, , , , and their ypropyl [3-cyclodextrin; 2-hydroxypropyl y-cyclodextrin; respective pharmaceutically acceptable derivatives, such as 2-hydroxybutyl [3-cyclodextrin; acetyl ot-cyclodextrin; beclomethasone diproprionate, dexamethasone 21-isonico acetyl [3-cyclodextrin; acetyl y-cyclodextrin; propionyl [3-cy tinate, icomethasone enbutate, tixocortol 21-pivalate, and clodextrin; butyryl [3-cyclodextrin; succinyl ot-cyclodextrin; . Particularly preferred are com succinyl [3-cyclodextrin; succinyl y-cyclodextrin; benZoyl pounds such as beclomethasone diproprionate, budesonide, [3-cyclodextrin; palmityl [3-cyclodextrin; toluenesulfonyl ?unisolide, ?uticasone propionate, mometasone and triam [3-cyclodextrin; acetyl methyl [3-cyclodextrin; acetyl butyl cinolone acetonide. In one embodiment, the steroid may be [3-cyclodextrin; glucosyl ot-cyclodextrin; glucosyl [3-cyclo present in the anti-in?ammatory steroid composition in an dextrin; glucosyl y-cyclodextrin; maltosyl ot-cyclodextrin; amount of from about 0.0001% to about 2.0% W/v. In maltosyl [3-cyclodextrin; maltosyl y-cyclodextrin; ot-cyclo another embodiment, the steroid may be present in the dextrin carboxymethylether; [3-cyclodextrin carboxymethyl anti-in?ammatory steroid composition in an amount of from ether; y-cyclodextrin carboxymethylether; carboxymethyl about 0.0005% to about 1.0% W/v. In yet another embodi ethyl [3-cyclodextrin; phosphate ester ot-cyclodextrin; ment, the steroid may be present in the anti-in?ammatory phosphate ester [3-cyclodextrin; phosphate ester y-cyclodex steroid composition in an amount of from about 0.001% to trin; 3-trimethylammonium-2-hydroxypropyl [3-cyclodex about 0.1% W/v. trin; sulfobutyl ether [3-cyclodextrin; carboxymethyl ot-cy [0028] The composition of the present invention includes clodextrin; carboxymethyl [3-cyclodextrin; carboxymethyl a cyclodextrin. Cyclodextrins are a group of structurally y-cyclodextrin, and combinations thereof. In one embodi related saccharides Which are formed by enZymatic cycliZa ment, the cyclodextrin may be present in the anti-in?am tion of starch by a group of amylases termed glycosyltrans matory steroid composition in an amount of from about ferases. Cyclodextrins are cyclic oligosaccharides, consist 0.1% to about 20% W/v. In another embodiment, the cyclo ing of (ot-1,4)-linked ot-D-glucopyranose units, With a dextrin may be present in the anti-in?ammatory steroid someWhat lipophilic central cavity and a hydrophilic outer composition in an amount of from about 1.0% to about 5% surface. The most common naturally occurring cyclodex W/v. In yet another embodiment, the cyclodextrin may be trins are ot-cyclodextrin, [3-cyclodextrin and y-cyclodextrin present in the anti-in?ammatory steroid composition in an consisting of 6, 7 and 8 glucopyranose units, respectively. Of amount of from about 1.5% to about 2.5 % W/v. Apreferred these three derivatives, [3-cyclodextrin appears to be the molar ratio of steroid to cyclodextrin ranges from about 1: 10 US 2006/0045850 A1 Mar. 2, 2006

to about 1:800, more preferably from about 1:25 to about [0034] The composition of the present invention includes 1:200, and most preferably from about 1:50 to about 1:100. an effective amount of a chelating agent. The term “chelat ing agent” refers to a compound or mixture of compounds [0031] The composition of the present invention includes used in a formulation. Chelating agents remove trace an alcohol co-solvent, such as propylene glycol, glycofurol, amounts of metal ions such as iron, copper and lead and acts ethoxydiglycol, ethyl alcohol, butyl alcohol, glycerin, hexy as antioxidant synergist as otherWise these heavy metals lene glycol, isopropyl alcohol, polyethylene glycol, polyhy catalyZe oxidation reactions. Presently preferred chelating dric alcohols, or combinations thereof. Polyhydric alcohols agents non-exclusively include different salts of edetic acid. are preferred as co-solvents and propylene glycol is most These non-exclusively include edetate disodium, edetate preferred. In one embodiment, the alcohol may be present in calcium disodium, edetate tetrasodium, edetate trisodium, the anti-in?ammatory steroid composition in an amount of and combinations thereof. In one embodiment, the chelating from about 0.2% to about 35% W/v. In another embodiment, agent may be present in the anti-in?ammatory steroid com the alcohol may be present in the anti-in?ammatory steroid position in an amount of from about 0.005% to about 0.1% composition in an amount of from about 0.2% to about W/v. In another embodiment, the chelating agent may be 10.0% W/v. In still another embodiment the alcohol may be present in the anti-in?ammatory steroid composition in an present in the anti-in?ammatory steroid composition in an amount of from about 0.01% to about 0.05% W/v. In yet amount of from about 1.0% to about 10.0% W/v. In yet another embodiment, the polyhydric alcohol may be present another embodiment, the chelating agent may be present in in the anti-in?ammatory steroid composition in an amount the anti-in?ammatory steroid composition in an amount of of from about 2.0% to about 5.0% W/v. from about 0.01% to about 0.02% W/v. [0032] The composition of the present invention includes [0035] In some cases, the composition of the present an effective amount of an antimicrobial preservative. Pre invention may include a crystalliZation inhibitor. This is servatives can be used to inhibit microbial groWth in the more often preferred With corticosteroids With higher compositions. An “effective amount” of a preservative is that molecular Weights such as (500.6) or amount necessary to prevent the groWth of microorganisms Beclomethasone dipropionate (539.06). Corticosteroids in the composition. The amount of preservative is generally With molecular Weights little loWer such as that Which is necessary to prevent microbial groWth in the 443.51 and Budenoside 430.5 usually do not require crys composition for a storage period of at least six months. talliZation inhibitor. Presently preferred crystalliZation Examples of pharmaceutically acceptable preservatives inhibitors non-exclusively include hydroxypropyl methyl include benZethonium chloride, butylparaben, methyl para cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, ben, ethyl paraben, propyl paraben, benZalkonium chloride, methyl cellulose, poly(2-propenoic acid), and other cellu cetyl pyridinium chloride, thimerosal, chlorobutanol, phe lose derivatives, and combinations of these cellulose deriva nylethyl alcohol, benZyl alcohol, potassium sorbate, sodium tives With loW viscosity grades. Hydroxy propyl methyl benZoate, sorbic acid or combinations thereof. In one cellulose of 6 cps or 3 cps grades may be used in the embodiment, the antibicrobial preservative may be present invention formulations. In one embodiment, the crystalliZa in the anti-in?ammatory steroid composition in an amount tion inhibitor may be present in the anti-in?ammatory ste of from about 0.002% to about 0.2% W/v. In another roid composition in an amount of from about 0.01% to about embodiment, the antibicrobial preservative may be present 10.0% W/v. In another embodiment, the crystalliZation in the anti-in?ammatory steroid composition in an amount inhibitor may be present in the anti-in?ammatory steroid of from about 0.005% to about 0.1% W/v. In yet another composition in an amount of from about 0.1% to about 5.0% embodiment, the antibicrobial preservative may be present W/v. In yet another embodiment, the crystalliZation inhibitor in the anti-in?ammatory steroid composition in an amount may be present in the anti-in?ammatory steroid composition of from about 0.01% to about 0.05% W/v. in an amount of from about 1.0% to about 2.5% W/v. [0033] The composition of the present invention includes [0036] The composition of the present invention then an effective amount of an antioxidant. The term “antioxi comprises sufficient Water to make-up the anti-in?ammatory dant” refers to a compound or mixture of compounds used steroid composition in the desired dosage. Preferably the in a formulation Which is useful for preventing the oxidation Water is pharmaceutical quality puri?ed Water. In one of active compound in a composition. An antioxidant must embodiment, the puri?ed Water may be present in the be pharmaceutically acceptable at the concentrations used, anti-in?ammatory steroid composition in an amount of from and should not interfere With the action of the active about 85.0% to about 98.0% by volume. In another embodi compound in the formulation. An “effective amount” of an ment, the puri?ed Water may be present in the anti-in?am antioxidant is that amount necessary to prevent undue oxi matory steroid composition in an amount of from about dation of the active compound under normal storage condi 90.0% to about 96% by volume. In yet another embodiment, tions. Presently preferred antioxidants are butylated the puri?ed Water may be present in the anti-in?ammatory hydroxyanisole, and to butylated hydroxytoluene. In one steroid composition in an amount of from about 93.0% to embodiment, the antioxidant may be present in the anti about 95.5% by volume. in?ammatory steroid composition in an amount of from about 0.0002 to about 0.5% W/v. In another embodiment, the [0037] The composition of the present invention then antioxidant may be present in the anti-in?ammatory steroid comprises an amount of a pH adjusting agent suf?cient to composition in an amount of from about 0.0002% to about adjust the pH of the composition to from about 4 to about 7, 0.05% W/v. In yet another embodiment, the antioxidant may preferably from about 4.5 to about 6.5 and more preferably be present in the anti-in?ammatory steroid composition in from about 5.0 to about 6.0. Preferred pH adjusting agents an amount of from about 0.002% to about 0.02% W/v. non-exclusively include citric acid, acetic acid, fumaric acid, US 2006/0045850 A1 Mar. 2, 2006

hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, and combinations thereof. Ingredient % quantity per 200 mL

[0038] The clear solution formulations are ?lled in to Beclomethasone dipropionate 0.020 0.04 g commercially available bottles and ?t With metered dose Hydroxypropyl [5-cyclodextrin 2.0 4.0 g pumps for nasal delivery of the drug products. Commer Citric acid, anhydrous 0.002 0.004 g Edetate disodium 0.01 0.02 g cially available metering pumps for nasal route application Propylene glycol 5.0 10.0 g are used to deliver the appropriate dose of corticosteroid per Hydroxypropyl methyl cellulose 2.0 4.0 g actuation. Such are available from Valois Pharmaceutical 6 cps grade Potassium sorbate 0.01 0.02 g Division, Pfeiffer of America, and Saint-Gobain Calmar, Puri?ed Water QS to 200 mL Inc. The delivery dose volumes of metered pumps may vary from about 25 microliters to about 200 microliters. [0043] Process: Place propylene glycol in a glass beaker [0039] The following non-limiting examples serve to and place the contents of the beaker in a hot Water bath illustrate the invention. maintained at a temperature of 60° C.-70° C. and add and dissolve beclomethasone under stirring. Continue stirring EXAMPLE 1 until it forms a clear solution. Separately dissolve hydrox ypropyl beta cyclodeXtrin in puri?ed Water 160 mL. To the Funisolide Nasal Solution cyclodeXtrin solution, add and dissolve under stirring [0040] This eXample describes the preparation of a nasal hydroXypropyl methyl cellulose and stir until it forms a clear solution form of ?unisolide in accordance With the methods solution. To this add beclomethasone dissolved in propylene of the present invention. Ingredients for the preparation of a glycol under stirring. Make solutions of edetate disodium in ?unisolide nasal solution of the invention are set forth in the puri?ed Water 10 mL, potassium sorbate in puri?ed Water 10 mL and citric acid in puri?ed Water 10 mL and add each table beloW. ingredient under stirring to the main bulk. Make up the volume to the batch siZe With puri?ed Water. Check and adjust the pH of the solution and ?lter the solution through Ingredient % quantity per 200 mL 0.45 micron nylon membrane ?lter.

Flunisolide 0.025 0.05 g EXAMPLE 3 Hydroxypropyl [5 CyclodeXtrin 1.5 3.0 g Citric Acid, Anhydrous 0.002 0.004 g Edetate Disodium 0.02 0.04 g Fluticasone Propionate Nasal Solution Propylene glycol 2.5 5.0 g Butylated hydroXy anisole 0.002 0.004 g [0044] This eXample describes the preparation of a nasal Cetyl pyridium chloride 0.05 0.1 g solution form of ?uticasone propionate in accordance With Puri?ed Water QS to 200 mL the methods of the present invention. Ingredients for the preparation of ?uticasone propionate nasal solution of the invention are set forth in the table beloW. [0041] Process: Propylene glycol is placed in a glass beaker and the contents of the beaker maintained in a hot Water bath at a temperature of 50-55° C. Add and dissolve ?unisolide under stirring. Continue stirring until it forms a Ingredient % quantity per 200 mL clear solution. Cool the solution to ambient temperature and Fluticasone propionate 0.005 0.010 g add and dissolve butylated hydroXy anisole. Separately Sulfobutyl ether [5 cyclodeXtrin 2.0 4.0 g Citric acid, anhydrous 0.002 0.004 g dissolve hydroXypropyl beta cyclodeXtrin in puri?ed Water Edetate disodium 0.02 0.04 g 160 mL. To this add the ?unisolide dissolved in propylene Propylene glycol 2.5 5.0 g glycol under stirring. Make solutions of edetate disodium in Hydroxypropyl methyl cellulose 2.0 4.0 g 6 cps grade puri?ed Water 10 mL, cetyl pyridinium chloride in puri?ed Potassium sorbate 0.01 0.02 g Water 10 mL and citric acid in puri?ed Water 10 mL and add Puri?ed Water QS to 200 mL each ingredient under stirring to the main bulk. Make up the volume With puri?ed Water to the batch siZe. Check and adjust the pH of the solution and ?lter the solution through [0045] Process: Place propylene glycol 5 .0 g and Water 0.5 a 0.45 micron nylon membrane ?lter. g miXture in a glass beaker and place the contents of the beaker in a hot Water bath maintained at a temperature of 60° EXAMPLE 2 C.-80° C. and add and dissolve ?uticasone propionate under stirring. Continue stirring until it forms a clear solution. Beclomethasone Dipropionate Nasal Solution Separately dissolve sulfobutyl ether beta cyclodeXtrin in puri?ed Water 160 mL. To this cyclodeXtrin solution, add [0042] This eXample describes the preparation of a nasal and dissolve under stirring hydroXypropyl methyl cellulose solution form of beclomethasone dipropionate in accordance and stir until it forms a clear solution. To this add ?uticasone With the methods of the present invention. Ingredients for dissolved in propylene glycol under stirring. Make solutions the preparation of beclomethasone dipropionate nasal solu of edetate disodium in puri?ed Water 10 mL, potassium tion of the invention are set forth in the table beloW. sorbate in puri?ed Water 10 mL and citric acid in puri?ed US 2006/0045850 A1 Mar. 2, 2006

Water 10 mL and add each ingredient under stirring to the passed through 0.45 micron acrodisk glass membrane ?lter main bulk. Make up the volume to the batch siZe With to remove any insoluble actives. puri?ed Water. Check and adjust the pH of the solution and ?lter the solution through 0.45 micron nylon membrane [0052] More than 98 percent assay values of the four examples indicate that the active steroids are in true solution ?lter. form. Even When stored at 8-15° C. the samples shoW assay values above 98 percent of the quantities added. EXAMPLE 4 [0053] While the present invention has been particularly Budenoside Nasal Solution shoWn and described With reference to preferred embodi [0046] This example describes the preparation of a nasal ments, it Will be readily appreciated by those of ordinary solution form of Budenoside in accordance With the methods skill in the art that various changes and modi?cations may of the present invention. Ingredients for the preparation of be made Without departing from the spirit and scope of the budenoside nasal solution of the invention are set forth in the invention. It is intended that the claims be interpreted to table beloW. cover the disclosed embodiment, those alternatives Which have been discussed above and all equivalents thereto. What is claimed is: Ingredient % quantity per 200 mL 1. An anti-in?ammatory steroid composition suitable for intranasal administration Which comprises: Budenoside 0.025 0.05 g Hydroxypropyl [5 cyclodextrin 2.0 4.0 g an anti-in?ammatory steroid in an amount of from about Citric acid 0.002 0.004 g 0.0001% to about 2.0% (W/v); Edetate disodium 0.01 0.02 g Propylene glycol 2.5 5.0 g a cyclodextrin in an amount of from about 0.1% to about Potassium sorbate 0.01 0.02 g 20% (W/v); Puri?ed Water QS to 200 mL an alcohol co-solvent in an amount of from about 0.2% to about 35% (W/v); [0047] Process: Place propylene glycol in a glass beaker an effective amount of an antimicrobial preservative; and place the contents of the beaker in a hot Water bath maintained at a temperature of 60° C.-70° C, and add and an effective amount of an antioxidant; dissolve ?unisolide under stirring. Continue stirring until it an effective amount of a chelating agent; forms a clear solution. Cool the solution to ambient tem perature. Water; and [0048] Separately dissolve hydroxypropyl beta cyclodex a pH adjusting agent suf?cient to adjust the pH of the trin in puri?ed Water 160 mL. To this add budenoside composition to from about 5 to about 7. dissolved in propylene glycol under stirring. Make solutions 2. The composition of claim 1 Wherein the alcohol co of edetate disodium in puri?ed Water 10 mL, potassium solvent is present in an amount of from about 0.2% to about sorbate in puri?ed Water 10 mL and citric acid in puri?ed 10% (W/v); Water 10 mL and add each ingredient under stirring to the 3. The composition of claim 1 Wherein the anti-in?am main bulk. Make up the volume With puri?ed Water to the matory steroid comprises aldosterone, beclomethasone, batch siZe. Check and adjust the pH of the solution and ?lter betamethasone, budesonide, cloprednol, cortisone, cortiva the solution through 0.45 micron nylon membrane ?lter. ZOl, deoxycortone, desonide, desoximetasone, dexametha sone, di?uorocortolone, ?uclorolone, ?umethasone, EXAMPLE 5 ?unisolide, ?uocinolone, ?uocinonide, ?uocortin butyl, ?uorocortisone, ?uorocortolone, ?uorometholone, ?uran Nasal Acceptability drenolone, ?uticasone, ?uticasone propionate, halcinonide, [0049] The folloWing example illustrates nasal acceptabil hydrocortisone, icomethasone, meprednisone, methylpred ity of the compositions of Examples 1-4. nisolone, mometasone paramethasone, mometasone furoate monohydrate, , prednisone, tixocortol, triamci [0050] A series of volunteers are randomly divided into nolone, beclomethasone diproprionate, dexamethasone four groups. Group 1 receives the composition of Example 21-isonicotinate, ?uticasone propionate, icomethasone enb 1, Group 2 receives the composition of Example 2, Group 3 utate, tixocortol 21-pivalate, and triamcinolone acetonide, or receives the composition of Example 3 and Group 4 receives combinations thereof. the composition of Example 4. The tests are performed by 4. The composition of claim 1 Wherein the anti-in?am applying one spray of the compositions to each nostril. matory steroid comprises ?unisolide, beclomethasone dipro Immediately after administration, no noticeable nasal sting pionate, budenoside, ?uticasone propionate, mometasone ing is noticed With the invention formulations. The results furoate or combinations thereof. indicate superior nasal acceptability for the nasally delivered 5. The composition of claim 1 Wherein the cyclodextrin drug compositions. comprises ot-cyclodextrin; [3-cyclodextrin; y-cyclodextrin; methyl ot-cyclodextrin; methyl [3-cyclodextrin; methyl y-cy EXAMPLE 6 clodextrin; ethyl [3-cyclodextrin; butyl ot-cyclodextrin; butyl [3-cyclodextrin; butyl y-cyclodextrin; pentyl y-cyclodextrin; Acceptable Recoveries: hydroxyethyl [3-cyclodextrin; hydroxyethyl y-cyclodextrin; [0051] Using liquid chromatographic run conditions, con 2-hydroxypropyl ot-cyclodextrin; 2-hydroxypropyl [3-cyclo tents of steroids in solution form are tested. The solutions are dextrin; 2-hydroxypropyl y-cyclodextrin; 2-hydroxybutyl US 2006/0045850 A1 Mar. 2, 2006

[3-cyclodeXtrin; acetyl ot-cyclodeXtrin; acetyl [3-cyclodeX citric acid, edetate disodium, propylene glycol, hydroXy trin; acetyl y-cyclodeXtrin; propionyl [3-cyclodeXtrin; propyl methyl cellulose and potassium sorbate. butyryl [3-cyclodeXtrin; succinyl ot-cyclodeXtrin; succinyl 15. The composition of claim 1 Which further comprises [3-cyclodeXtrin; succinyl y-cyclodeXtrin; benZoyl [3-cyclo a crystalliZation inhibitor. deXtrin; palmityl [3-cyclodeXtrin; toluenesulfonyl [3-cyclo 16. The composition of claim 1 Which further comprises deXtrin; acetyl methyl [3-cyclodeXtrin; acetyl butyl [3-cyclo a crystalliZation inhibitor in an amount of 0.5% to about deXtrin; glucosyl ot-cyclodeXtrin; glucosyl [3-cyclodeXtrin; 5.0% W/v. glucosyl y-cyclodeXtrin; maltosyl ot-cyclodeXtrin; maltosyl 17. The composition of claim 1 Which further comprises [3-cyclodeXtrin; maltosyl y-cyclodeXtrin; ot-cyclodeXtrin car a crystalliZation inhibitor selected from the group consisting boXymethylether; [3-cyclodeXtrin carboXymethylether; y-cy of hydroXypropyl methyl cellulose, hydroXyethyl cellulose, clodeXtrin carboXymethylether; carboXymethylethyl [3-cy hydroXypropyl cellulose, methyl cellulose, poly(2-prope clodeXtrin; phosphate ester ot-cyclodeXtrin; phosphate ester noic acid), and combinations thereof. [3-cyclodeXtrin; phosphate ester y-cyclodeXtrin; 3-trimethy 18. A method of treating in?ammation of the nasal lammonium-2-hydroXypropyl [3-cyclodeXtrin; sulfobutyl mucosa, Which method comprises intranasally administering ether [3-cyclodeXtrin; carboXymethyl ot-cyclodeXtrin; car to a subject in need thereof an anti-in?ammatory steroid boXymethyl [3-cyclodeXtrin; carboXymethyl y-cyclodeXtrin, composition comprising: and combinations thereof. 6. The composition of claim 1 Wherein the cyclodeXtrin an anti-in?ammatory steroid in an amount of from about comprises hydroXypropyl [3-cyclodeXtrin, sulfobutyl ether 0.0001% to about 2.0% (W/v); a cyclodeXtrin in an amount of from about 0.1% to about 20% (W/v); [3-cyclodeXtrin, or combinations thereof. 7. The composition of claim 1 Wherein the alcohol co an alcohol in an amount of from about .2% to about 35% solvent comprises propylene glycol, glycofurol, ethoXydig (W/v); lycol, ethyl alcohol, butyl alcohol, glycerin, heXylene glycol, isopropyl alcohol, polyethylene glycol, polyhydric alcohols, an effective amount of an antimicrobial preservative; or combinations thereof. an effective amount of an antioxidant; 8. The composition of claim 1 Wherein the antibicrobial preservative comprises benZethonium chloride, butylpara an effective amount of a chelating agent; ben, methyl paraben, ethyl paraben, propyl paraben, benZa Water; and lkonium chloride, cetyl pyridinium chloride, thimerosal, chlorobutanol, phenylethyl alcohol, benZyl alcohol, potas a pH adjusting agent sufficient to adjust the pH of the sium sorbate, sodium benZoate, sorbic acid or combinations composition to from about 5 to about 7. thereof. 19. The method of claim 18 Wherein the anti-in?amma 9. The composition of claim 1 Wherein the chelating agent tory steroid composition comprises ?unisolide, hydroXypro comprises a salt of editic acid, or combinations thereof. pyl cyclodeXrin, citric acid, edetate disodium, propylene 10. The composition of claim 1 Wherein the pH adjusting glycol, butylated hydroXy anisole, and cetyl pyridium chlo agent comprises citric acid, acetic acid, fumaric acid, hydro ride. chloric acid, malic acid, nitric acid, phosphoric acid, propi 20. The method of claim 18 Wherein the anti-in?amma onic acid, sulfuric acid, tartaric acid, or combinations tory steroid composition comprises beclomethasone dipro thereof. pionate, hydroXypropyl cyclodeXtrin, anhydrous citric acid, 11. The composition of claim 1 Which comprises edetate disodium, propylene glycol, hydroXy propyl methyl ?unisolide, hydroXypropyl [3-cyclodeXrin, citric acid, ede cellulose and potassium sorbate. tate disodium, propylene glycol, butylated hydroXy anisole, 21. The method of claim 18 Wherein the anti-in?amma and cetyl pyridium chloride. tory steroid composition comprises budenoside, hydrox 12. The composition of claim 1 Which comprises beclom ypropyl cyclodeXrin, citric acid, edetate disodium, propy ethasone dipropionate, hydroXypropyl [3-cyclodeXtrin, anhy lene glycol, and potassium sorbate. drous citric acid, edetate disodium, propylene glycol, 22. The method of claim 18 Wherein the anti-in?amma hydroXy propyl methyl cellulose and potassium sorbate. tory steroid composition comprises ?uticasone propionate, 13. The composition of claim 1 Which comprises bude sulfobutyl ether beta cyclodeXtrin, anhydrous citric acid, noside, hydroXypropyl [3-cyclodeXrin, citric acid, edetate edetate disodium, propylene glycol, hydroXy propyl methyl disodium, propylene glycol, and potassium sorbate. cellulose and potassium sorbate. 14. The composition of claim 1 Which comprises ?utica sone propionate, sulfobutyl ether [3-cyclodeXtrin, anhydrous * * * * *