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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 STEROIDS (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 steroid 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, mometasone 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® (Fluticasone 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 corticosteroids 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 corticosteroid. 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 glucocorticoids and mineralocorticoids, and synthetic ana cyclodextrin complex solution.
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