(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`10 January 2008 (10.01.2008)
`
`
`
`(10) International Publication Number
`WO 2008/005053 Al
`
`(51) International Patent Classification:
`A6IK 9/00 (2006.01)
`CO8B 37/16 (2006.01)
`
`(74) Agent: MATOS, Rick; Innovar, LLC, P.O. Box 250647,
`Plano, TX 75025-0647 (US).
`
`(21) International Application Number:
`PCT/US2006/062346
`
`(22) International Filing Date:
`20 December 2006 (20.12.2006)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`11/479,979
`.
`.
`.
`(71) Applicant (for all designated States except US): CYDEX,
`INC, [US/US]; 10513 W. 84th Terrace, Lenexa, KS 66214
`(US).
`
`30 June 2006 (30.06.2006)
`
`US
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): PIPKIN, James, D.
`[US/US]; 4500 Woodland Dr., Lawrence, KS 66049 (US).
`ZIMMERER, Rupert, O. [US/US]; 1162 North 1100
`Rd., Lawrence, KS 66047 (US). THOMPSON,Diane,O.
`[US/US]; P.O. Box 410432, Kansas City, MO 64108 (US).
`MOSHER, Gerold, L.
`[US/US]; 12215 Avila Drive,
`Kansas City, MO 64145 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES,FI,
`GB, GD, GE, GH, GM, GT, HN, HR, HU,ID,IL, IN,IS,
`JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS,
`LT, 1.U, LV, LY, MA, MD, MG, MK, MN, MW, MX,MY,
`MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS,
`RU, SC, SD,SE, SG, SK, SL, SM,SV, SY, TJ, TM, TN,
`TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES,EI,
`FR, GB, GR,HU,IE, IS, IT, LT, LU, LV, MC, NL, PL,PT,
`RO, SE, SI, SK, TR), OAPI (BE, BJ, CK, CG, Cl, CM, GA,
`GN, GO, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`with international search report
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes and Abbreviations” appearing at the begin-
`ning of each regular issue of the PCT Gazette.
`
`(54) Title:
`TEROID
`
`INHALANT FORMULATION CONTAINING SULFOALKYL ETHER CYCLODEXTRIN AND CORTICOS-
`
`‘The formulation is adapted for ad-
`& (87) Abstract: An inhalable formulation containing SAE-CD andcorticosteroid is provided.
`©} ministration to a subject by nebulization with any known nebulizer. The formulation can be included in a kit. The formulation is
`administered as an aqueous solution, however, it can be stored as a dry powder, ready-to-use solution, or concentrated composition.
`The formulation is employed in an improved nebulization system for administering corticosteroid by inhalation. SAE-CD presentin
`the formulation significantly enhances the chemicalstability of budesonide. A method of administering the formulation by inhalation
`is provided. The formulation can also be administered by conventional nasal delivery apparatus.
`
`WO2
`
`
`
`
`
`8/005053AdIMMMINNUNTINTININMATCAAIAMMII
`
`

`

`WO 2008/005053
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`PCT/US2006/062346
`
`-1-
`
`Inhalant Formulation Containing Sulfoalkyl Ether Cyclodextrin
`
`and Corticosteroid
`
`BY:
`
`James D. Pipkin, Rupert O. Zimmerer, Diane O. Thompson, Gerold L. Mosher
`
`CROSS-REFERENCE TO EARLIER FILED APPLICATIONS
`
`The present application is a continuation-in-part of and claims the priority of U.S.
`
`application No. 11/479,979 filed June 30, 2006.
`
`FIELD OF THE INVENTION
`
`The present
`
`invention relates to methods of and systems for administering
`
`formulations of sulfoalkyl ether cyclodextrin and corticosteroid, such as budesonide, by
`
`nebulization and inhalation. The invention also relates to methods of treating respiratory
`
`diseases or disorders of the air passageways.
`
`BACKGROUND OF THE INVENTION
`
`10
`
`The delivery of a drug by inhalation allows deposition of the drug in different
`
`sections of the respiratory tract, e.g., throat, trachea, bronchi and alveoli. Generally, the
`
`smaller the particle size, the longer the particle will remain suspendedin air and the farther
`
`down the respiratory tract the drug can be delivered. Corticosteroids are delivered by
`
`inhalation using nebulizers, metered dose inhalers, or dry powder inhalers. The principle
`
`15
`
`advantages of nebulizers over other methods of pulmonary installation are that patient
`
`cooperation is not required and the delivery of higher doses of medication is easier. The
`
`main concerns about nebulizers, however, are their increased cost, reduced portability and
`
`the inconvenience of needing to prepare medication beforehand and the increased time
`
`requirement for administering a treatment. A method of improving the administration of
`
`20
`
`drugs, such as corticosteroids by nebulization would be desired.
`
`Budesonide ((R,S)-118, 160, 17, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione
`
`cyclic 16, 17-acetal with butyraldehyde; C25H3406; Mw: 430.5) is well known.
`
`It is
`
`provided commercially as a mixture of two isomers (22R and 22S). Budesonideis an anti-
`
`inflammatory corticosteroid that exhibits potent glucocorticoid activity. Administration of
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`WO 2008/005053
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`
`-2-
`
`budesonide is indicated for maintenance treatment of asthma and as prophylactic therapy
`
`in children.
`
`Commercial formulations of budesonide are sold by AstraZeneca LP (Wilmington,
`
`DE) under the trademarks ENTOCORT™ EC, PULMICORT RESPULES®, Rhinocort
`
`Aqua®, Rhinocort® Nasal Inhaler and Pulmicort Turbuhaler®, and under its generic
`
`name. PULMICORT RESPULES® suspension, which is a sterile aqueous suspension of
`
`micronized budesonide,
`
`is administered by inhalation using a nebulizer, in particular a
`
`compressed air driven jet nebulizer that delivers from 2 to 18% of the drug mass contained
`
`in the nominal charge. The general formulation for a unit dose of the PULMICORT
`
`10
`
`RESPULESis set forth in U.S. Patent No. 6,598,603, and it is an aqueous suspension in
`
`which budesonide is suspended in an aqueous medium comprising about 0.05 to 1.0 mg of
`
`budesonide, 0.05 to 0.15 mg of NaEDTA, 8.0 to 9.0 mg of NaCl, 0.15 to 0.25 mg of
`
`polysorbate, 0.25 to 0.30 mg of anhydrous citric acid, and 0.45 to 0.55 mg of sodium
`citrate per one ml of water. RHINOCORT® NASAL INHALER™is a metered-dose
`
`15
`
`pressurized aerosol unit containing a suspension of micronized budesonide in a mixture of
`propellants. RHINOCORT® AQUA"is an unscented metered-dose manual-pump spray
`
`formulation containing a suspension of micronized budesonide in an aqueous medium.
`
`The suspensions should not be administered with an ultrasonic nebulizer.
`
`A wide variety of nebulizers differing in mode of operation are available, e.g. jet
`
`20
`
`nebulizers (optionally sold with compressors), ultrasonic nebulizers, vibrating membrane,
`
`vibrating mesh nebulizers, vibrating plate nebulizers, vibrating cone nebulizers, and
`
`others. The vibrating mesh, vibrating cone or vibrating plate nebulizers are of particular
`
`interest since they do not require the use of an air compressor for delivery, have a minimal
`
`residual volume in the reservoir after delivery of a unit dose, and can be used to deliver
`
`25
`
`low volumes of inhalable solutions. Exemplary vibrating membrane, mesh or plate
`
`nebulizers are described by R. Dhand (Respiratory Care, (Dec. 2002), 47(12), p. 1406-
`1418). Keller et al. (ATS 99" International Conference, Seattle, May 16-21%, 2003;
`
`poster 2727) disclose the results of a study on the administration of AZTREONAM with a
`
`PARI eFlow nebulizer and report low oropharyngeal deposition, nebulization efficiency
`
`30
`
`unaffected by fill volume, a respirable fraction of 8241.7%, constant dose administration
`
`per inhalation cycle time, and an excellent correlation between delivered dose, fill volume
`
`and nebulization time, and expected high lung deposition.
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`-3-
`
`The desired properties of a liquid for nebulization generally include: 1) reduced
`
`viscosity; 2) sterile medium; 3) reduced surface tension; 4) stability toward the mechanism
`
`of the nebulizer; 5) moderate pH of about 4-10; 6) ability to form droplets with an MMAD
`
`of <5 um or preferably <3 Um; 7) absence of iritating preservatives and stabilizing
`
`agents; 8) suitable tonicity. On the one hand, suspensions possess some advantages but on
`
`the other hand solutions possess other advantages.
`
`Smaldone et al. (J. Aerosol Med. (1998), 11, 113-125) disclose the results of a
`
`study on the im vitro determination of inhaled mass and particle distribution of a
`
`budesonide suspension.
`
`They conclude that 2%-18% of the nebulizer’s charge of
`
`10
`
`budesonide was delivered from the suspension, meaning that budesonide delivery was
`
`incomplete resulting in a significant waste of drug.
`
`In the thirteen most efficient systems,
`
`the suspension can be nebulized sufficiently well for lower respiratory tract delivery.
`
`Another study further demonstrated the highly variable efficiency of nebulization
`
`from one nebulizer to another. Barry et al. (J. Allergy Clin. Immunol. (1998), 320-321)
`
`15
`
`state that
`
`this variability should be taken into account when treating patients with
`
`nebulized budesonide. Berg et al. (J. Aerosol Sci. (1998), 19(7), 1101-1104) also report
`
`the highly variable efficiency of nebulization of PULMICORT™suspension from one
`
`nebulizer to the next. Moreover, the mass mean aerodynamic diameter (MMAD) of the
`
`nebulized droplets is highly variable from one nebulizer to the next.
`
`In general,
`
`20
`
`suspensions are less efficiently nebulized than solutions, O’Riordan (Respiratory Care,
`
`(2002), 1305-1313).
`
`Inhaled corticosteroids are utilized in the treatment of asthma and are
`
`of significant benefit because they are delivered directly to the site of action, the lung. The
`
`goal of an inhaled corticosteroid is to provide localized therapy with immediate drug
`
`activity in the lungs.
`
`Inhaled corticosteroids are well absorbed from the lungs. In fact, it
`
`25
`
`can be assumed that all of the drug available at the receptor site in the lungs will be
`
`absorbed systemically.
`
`However, it is well known that using current methods and
`
`formulations the greater part of an inhaled corticosteroid dose is swallowed and becomes
`
`available for oral absorption,
`
`resulting in unwanted systemic effects.
`
`For
`
`inhaled
`
`corticosteroids, high pulmonary availability is more
`
`important
`
`than high oral
`
`30
`
`bioavailability because the lung is the target organ. A product with high pulmonary
`
`availability has greater potential to exert positive effects in the lung. The ideal inhaled
`
`corticosteroid formulation would provide minimum oral delivery thereby reducing the
`
`likelihood of systemic adverse effects.
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`-4-
`
`The majority of the corticosteroid dose delivered to the lung is absorbed and
`
`available systemically. For the portion of the inhaled corticosteroid dose delivered orally,
`
`bioavailability depends upon absorption from the GI tract and the extent of first pass
`
`metabolism in the liver. Since this oral component of corticosteroid drug delivery does not
`
`provide any beneficial
`
`therapeutic effect but can increase systemic side effects,
`
`it is
`
`desirable for the oral bioavailability of inhaled corticosteroid to be relatively low.
`
`Both particle size
`
`and formulation influence the efficacy of an inhaled
`
`corticosteroid. The formulation of a drug has a significant impact on the delivery of that
`
`drug to the lungs, and therefore its efficacy. Most important in the delivery of drug to the
`
`10
`
`lung are the aerosol vehicle and the size of the particles delivered. Additionally, a reduced
`
`degree of pulmonary deposition suggests a greater degree of oropharyngeal deposition.
`
`Due to a particular formulation employed, some corticosteroids are more likely to be
`
`deposited in the mouth and throat and may cause local adverse effects.
`
`While receptor distribution is the major determinant of bronchodilator efficacy,
`
`15
`
`particle size appears to be more important in determining the efficacy of an inhaled
`
`corticodsteroid. The smallest airways have an internal diameter of 2 micrometers (mcm)
`
`or less. Thus, an inhaler with particles having a mean aerodynamic diameter of 1 mcm
`
`should have a greater respirable fraction than an inhaler with particles that have an average
`
`diameter of 3.5 to 4 mcm. For patients with obstructive lung disease, all particles should
`
`20
`
`ideally be no greater than 2 to 3 mcm. A particle that is small (less than 5 mcm) is more
`
`likely to be inhaled into the smaller airways of the lungs, thus improving efficacy. In
`
`contrast, particles that are larger than 5 mcm can be deposited in the mouth andthroat,
`
`both reducing the proportion of particles that reach the lungs and potentially causing local
`
`adverse effects such as oral candidiasis and hoarseness (dysphonia). Particles having a
`
`25
`
`mass median aerodynamic diameter (MMAD) of close to 1 mcm are considered to have a
`
`greater respirable fraction per dose than those with a diameter of 3.5 mcm orgreater.
`
`A further disadvantage to the nebulization of budesonide suspensions is the need to
`
`generate very small droplets, MMADof about <3 um. Since the nebulized droplets are so
`
`small, then the micronized budesonide must be even smaller or in the range of 0.5-2.0 um
`
`30
`
`and the particles should have a narrow particle size distribution. Generation of such
`
`particles is difficult.
`
`Even so, efforts have been made to improve the nebulization of budesonide
`
`suspensions with ultrasonic nebulizers by using submicron-sized particles (Keller et al. in
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`-5-
`
`Respiratory Drug Delivery VIII (2002), 197-206). A suspension of nanoparticles (0.1-1.0
`
`lum) of the corticosteroid might be used to increase the proportion of respirable particles as
`
`compared to a coarser suspension as in the PULMICORT™suspension. No improvement
`
`over PULMICORT™suspension (about 4.4 um budesonide particle size in suspension)
`
`was observed. Moreover, concerns exist regarding the use of nanosuspensionsin that the
`
`small particles (<0.05 Um) may induce an allergic response in a subject.
`
`Sheffield
`
`Pharmaceuticals, Inc. (St. Louis, MO; “The Pharmacokinetics of Nebulized Nanocrystal
`
`Budesonide Suspension in Healthy Volunteers”, Kraft, et al.
`
`in J. Clin. Pharmacol.,
`
`(2004), 44:67-72) has disclosed the preparation and evaluation of UDB (unit dose
`
`10
`
`budesonide), which is a suspension-based formulation containing nanoparticles of
`
`budesonide dispersed in a liquid medium. This product is being developed by MAP
`Pharmaceuticals, Inc. (Mountain View, California). Seeman et al. (ATS 99" International
`Conference, Seattle, May 16-21%, 2003; poster 2727) disclose the results of a study
`
`evaluating the performance of the PARI eFlow nebulizer with a budesonide suspension
`
`15
`
`(PULMICORT RESPULES, 500 ug/ml,
`
`in a 2 ml ampoule) and report achieving a
`
`MMADof3.6-4.2 ium and a respirable fraction of greater than 67%.
`
`The inhalation of drug particles as opposed to dissolved drug is known to be
`disadvantageous. Brain et al. (Bronchial Asthma, 2™ Ed. (Ed. E.B. Weis et al., Little
`
`Brown & Co, (1985), pp. 594-603) report that less soluble particles that deposit on the
`
`20
`
`mucous blanket covering pulmonary airways and the nasal passages are moved toward the
`
`pharynx by the cilia. Such particles would include the larger drug particles deposited in
`
`the upper respiratory tract. Mucus, cells and debris coming from the nasal cavities and the
`
`lungs meet at the pharynx, mix with saliva, and enter the gastrointestinal tract upon being
`
`swallowed. Reportedly, by this mechanism, particles are removed from the lungs with
`
`25
`
`half-times of minutes to hours. Accordingly,
`
`there is little time for solubilization of
`
`slowly dissolving drugs, such as budesonide.
`
`In contrast, particles deposited in the
`
`nonciliated compartments, such as the alveoli, have much longer residence times. Sinceit
`
`is difficult to generate very small particles of budesonide for deep lung deposition, much
`
`of the inhaled suspension would likely be found in the upper to middle respiratory tract.
`
`30
`
`However, it is much easier to generate small droplets from a solution than it is from a
`
`suspension of solids. For these reasons, nebulization of a budesonide-containing solution
`
`should be preferred over that of a suspension.
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`-6-
`
`O’ Riordan (Respiratory Care (2002 Nov), 47(11), 1305-1313) states that drugs can
`
`be delivered by nebulization of either solutions or suspensions, but that
`
`in general,
`
`nebulization of a solution is preferred over that of a suspension. Hestates that ultrasonic
`
`nebulizers should not be used on suspensions and should be used only on solutions.
`
`O’Callaghan (Thorax, (1990), 45, 109-111), Storr et al. (Arch. Dis. Child (1986),
`
`61, 270-273), and Webb et al. (Arch. Dis. Child (1986), 61, 1108-1110) suggest that
`
`nebulization of corticosteroid (in particular beclomethasone) solutions may be preferred
`
`overthat of suspensions because the latter may be inefficient if the nebulized particles are
`
`too large to enter the lung in therapeutically effective amounts. However, data presented
`
`10
`
`by O’Callaghan (J. Pharm. Pharmacol.
`
`(2002), 54, 565-569) on the nebulization of
`
`flunisolide solution versus
`
`suspension showed that
`
`the two performed similarly.
`
`Therefore, it cannot be generalized that nebulization of a solution is preferred over that of
`
`a suspension.
`
`Accordingly, there is a widely recognized need for a non-suspension formulation
`
`15
`
`comprising a corticosteroid for administration via nebulization.
`
`However,
`
`the
`
`PULMICORT®suspension unit dose formulation is widely available and accepted in the
`
`field of inhalation therapy.
`
`It would be of great benefit to this field of therapy to provide a
`
`method of improving the administration of the PULMICORT® suspension unit dose
`
`formulation, or more generally, of a suspension unit dose formulation containing a
`
`20
`
`corticosteroid.
`
`However,
`
`the current
`
`focus
`
`in nebulizer
`
`therapy is
`
`to administer higher
`
`concentrations of drug, use solution, preferably predominantly aqueous-based solutions in
`
`preference to non-aqueousor alcoholic or non-aqueous alcoholic solutions or suspensions
`
`if possible, minimize treatment
`
`time, synchronize nebulization with inhalation, and
`
`25
`
`administer smaller droplets for deeper lung deposition of drug.
`
`Corticosteroid-containing solutions for nebulization are known.
`
`There are a
`
`numberof different ways to prepare solutions for nebulization. These generally have been
`
`prepared by the addition of a cosolvent, surfactant, or buffer. However, cosolvents, such
`
`as ethanol, polyethylene glycol and propylene glycol are only tolerated in low amounts
`
`30
`
`when administered by inhalation due to irritation of the respiratory tract. There are limits
`
`to acceptable levels of these cosolvents in inhaled products. Typically,
`
`the cosolvents
`
`make up less than about 35% by weight of the nebulized composition, although it is the
`
`total dose of cosolvent as well as its concentration that determines these limits. The limits
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`-7-
`
`are set by the propensity of these solvents either to cause local irritation of lung tissue, to
`
`form hyperosmotic solutions that would draw fluid into the lungs, and/or to intoxicate the
`
`patient. In addition, most potential hydrophobic therapeutic agents are not sufficiently
`
`soluble in these cosolvent mixtures.
`
`Saidi et al. (U.S. Patent No. 6,241,969) disclose the preparation of corticosteroid-
`
`containing solutions for nasal and pulmonary delivery. The dissolved corticosteroids are
`
`present
`
`in a concentrated, essentially non-aqueous form for storage or in a diluted,
`
`aqueous-based form for administration.
`
`Keller et al. Gn Respiratory Drug Delivery [IX (2004) 221-231) disclose the
`
`10
`
`deposition of solution formulations containing budesonide and surfactants to children.
`
`Lintz et al. (AAPS Annual Meeting and Exposition, Baltimore, Nov. 8, 2004;
`
`Poster M1128) disclose the preparation and aerosol characterization of liquid formulations
`
`containing budesonide, water, citrate salt, sodium chloride and alcohol, propylene glycol
`
`and/or surfactant, such as Tween, Pluronic, or phospholipids with HLB-values between 10
`
`15
`
`and 20. The aerosol characterization of such a combination surfactant solution in a
`
`vibrating membrane/mesh nebulizer (the Pari eFlow) compared to a suspension was
`
`studied using adult and child breath simulation.
`
`They reported a respirable fraction of
`
`83.3% for the PARI eFlow with the solution and 61% for the PULMICORT RESPULES
`
`with the PARI LC+. They also reported the results regarding the respirable drug delivery
`
`20
`
`rate (% drug < 5tm/min), delivered dose (% of drug charged to device), drug delivery rate
`
`(% drug/min), and respirable dose (% < 5m).
`Schueepp et al. (ATS 99" International Conference, Seattle, May 16-21%, 2003;
`
`poster 1607) disclose assessment of the aerosol performance of a customized eFlow Baby
`
`Functional Model with an experimentalbudesonide solution (100 ug in 0.5 ml) utilizing a
`
`25
`
`baby cast model and applying different breathing patterns. .
`
`An alternative approach to administration of the PULMICORT™ suspension is
`
`administration of a liposome formulation. Waldrep et al. (J. Aerosol Med. (1994), 7(2),
`
`135-145) reportedly succeeded in preparing a liposome formulation of budesonide and
`
`phosphatidylcholine derivatives.
`
`30
`
`Noneof the above-identified formulations has provided a method of improving the
`
`administration of a suspension-based unit dose formulation containing a corticosteroid.
`
`Instead, the general focus of the art has been to completely circumvent formulating a
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`-8-
`
`suspension by first preparing a liquid formulation that is then divided into multiple unit
`
`doses that are packaged for marketing and then sold for use.
`
`Solubilization of drugs by cyclodextrins and their derivatives is well known.
`
`Cyclodextrins
`
`are
`
`cyclic
`
`carbohydrates derived from starch.
`
`The unmodified
`
`cyclodextrins differ by the number of glucopyranose units joined together in the
`
`cylindrical structure. The parent cyclodextrins contain 6, 7, or 8 glucopyranose units and
`
`are referred to as a-, B-, and y-cyclodextrin respectively. Each cyclodextrin subunit has
`
`secondary hydroxyl groups at the 2 and 3 positions and a primary hydroxyl group at the
`
`6-position. The cyclodextrins may be pictured as hollow truncated cones with hydrophilic
`
`10
`
`exterior
`
`surfaces and hydrophobic interior cavities.
`
`In aqueous
`
`solutions,
`
`these
`
`hydrophobic cavities provide a haven for hydrophobic organic compoundsthat canfit all
`
`or part of
`
`their
`
`structure into these cavities. This process, known as
`
`inclusion
`
`complexation, may result in increased apparent aqueous solubility and stability for the
`
`complexed drug. The complex is stabilized by hydrophobic interactions and does not
`
`15
`
`involve the formation of any covalent bonds.
`
`This dynamic and reversible equilibrium process can be described by Equations 1
`
`and 2, where the amount in the complexed form is a function of the concentrations of the
`
`drug and cyclodextrin, and the equilibrium or binding constant, Ky. When cyclodextrin
`
`formulations are administered by injection into the blood stream, the complex rapidly
`
`20
`
`dissociates due to the effects of dilution and non-specific binding of the drug to blood and
`
`tissue components.
`
`Drug + Cyclodextrin —**—» Complex
`
`Equation 1
`
`[Complex]
`Ke=
`Equation
`2
`25
`
`
`. Drug||Cyclodextrin quation
`
`Binding constants of cyclodextrin and an active agent can be determined by the
`
`equilibrium solubility technique (T. Higuchi et al. in “Advances in Analytical Chemistry
`
`and Instrumentation Vol. 4”; C.N. Reilly ed.; John Wiley & Sons, Inc, 1965, pp. 117-212).
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`30
`
`Generally, the higher the concentration of cyclodextrin, the more the equilibrium process
`
`of Equations 1 and 2 is shifted to the formation of more complex, meaning that the
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`concentration of free drug is generally decreased by increasing the concentration of
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`cyclodextrin in solution.
`
`The underivatized parent cyclodextrins are known to interact with human tissues
`
`and extract cholesterol and other membrane components, particularly upon accumulation
`
`in the kidney tubule cells, leading to toxic and sometimes fatal renal effects.
`
`The parent cyclodextrins often exhibit a differing affinity for any given substrate.
`
`For example, y-cyclodextrin often forms complexes with limited solubility, resulting in
`
`solubility curves of the type Bs. This behavior is known for a large number of steroids
`
`which imposesserious limitations towards the use of y-CD in liquid preparations. B-CD,
`
`10
`
`however, does not complex well with a host of different classes of compounds.
`
`It has
`
`been shown for B-CD and y-CD that derivatization, e.g. alkylation, results in not only
`
`better aqueous solubility of the derivatives compared to the parent CD, but also changes
`
`the type of solubility curves from the limiting Bs-type to the more linear A-type curve
`
`(Bernd W. Muller and Ulrich Brauns, “Change of Phase-Solubility Behavior by Gamma-
`
`15
`
`Cyclodextrin Derivatization’, Pharmaceutical Research (1985) p 309-310).
`
`Chemical modification of the parent cyclodextrins (usually at the hydroxyls) has
`
`resulted in derivatives with improved safety while retaining or
`
`improving the
`
`complexation ability. Of the numerous derivatized cyclodextrins prepared to date, only
`
`two appear to be commercially viable:
`
`the 2-hydroxypropyl derivatives (HP-CD; neutral
`
`ROCH,
`
`ROCH,
`
`ROCH,
`
`4SO CH5OR
`
`RO
`
`RO
`
`CH,OR
`
`OR
`
`ORSnape
`
`0
`ROCH,
`
`Ome ‘CHSOR
`
`Sulfobutyl Ether-B-Cyclodextrin (Captisol®)
`cyclodextrins being commercially developed by Janssen and others), and the sulfoalkyl
`
`20
`
`ether derivatives,
`
`such as
`
`sulfobutyl ether,
`
`(SBE-CD; anionic cyclodextrins being
`
`R=(-H)21-, or (-(CH2)4-SO3Na),
`where n=6.0-7.1
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`developed by CyDex, Inc.) However,
`
`the HP-B-CD still possesses toxicity that
`
`the
`
`SBE-CDdoes not.
`
`U.S. Patents No. 5,376,645 and No. 5,134,127 to Stella et al., U.S. Patent No.
`
`3,426,011 to Parmerter et al., Lammers et al. (Recl. Trav. Chim. Pays-Bas (1972), 91(6),
`
`733-742); Staerke (1971), 23(5), 167-171) and Qu et al. (/. Inclusion Phenom. Macro.
`
`Chem., (2002), 43, 213-221) disclose sulfoalkyl ether derivatized cyclodextrins. The
`
`references suggest that SAE-CD should be suitable for solubilizing a range of different
`
`compounds. However, Stella discloses that the molar ratio of sulfoalkyl ether derivatized
`
`cyclodextrin to active ingredient suitable for solubilization of the active ingredient, even a
`
`10
`
`corticosteroid, in water ranges from 10:1 to 1:10.
`
`A sulfobutyl ether derivative of beta cyclodextrin (SBE-B-CD), in particular the
`
`derivative with an average of about 7 substituents per cyclodextrin molecule (SBE7-B-
`CD), has been commercialized by CyDex, Inc. as CAPTISOL®. The anionic sulfobutyl
`
`ether substituent dramatically improves the aqueous solubility of the parent cyclodextrin.
`
`15
`
`In addition, the presence of the charges decreases the ability of the molecule to complex
`
`with cholesterol as compared to the hydroxypropyl derivative. Reversible, non-covalent,
`complexation of drugs with CAPTISOL® cyclodextrin generally allows for increased
`solubility and stability of drugs in aqueous solutions. While CAPTISOL isa relatively
`
`new but known cyclodextrin,
`
`its use in the preparation of corticosteroid-containing
`
`20
`
`solutions for nebulization has not previously been evaluated.
`
`Hemolytic assays are generally used in the field of parenteral formulations to
`
`predict whether or not a particular formulation is likely to be unsuitable for injection into
`
`the bloodstream of a subject.
`
`If the formulation being tested induces a significant amount
`
`of hemolysis, that formulation will generally be considered unsuitable for administration
`
`25
`
`to a subject.
`
`It is generally expected that a higher osmolality is associated with a higher
`
`hemolytic potential. As depicted in FIG.
`
`1
`
`(Thompson, D.O., Critical Reviews in
`
`Therapeutic Drug Carrier Systems, (1997), 14(1), 1-104), the hemolytic behavior of the
`CAPTISOL® is compared to the same for the parent B-cyclodextrin, the commercially
`
`
`
`
`
`available IEENCAPSIN™~~cyclodextrinhydroxypropyl derivatives, (degree of
`
`substitution~3-4) and MOLECUSOL® cyclodextrin (degree of substitution~7-8), and two
`
`30
`
`other sulfobutyl ether derivatives, SBE1-B-CD and SBE4-B-CD. Unlike the other
`
`cyclodextrin derivatives, sulfoalkyl ether (SAE-CD) derivatives, in particular those such
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`as the CAPTISOL® (degree of substitution~7) and SBE4-B-CD (degree of substitution~4),
`
`show essentially no hemolytic behavior and exhibit substantially lower membrane
`
`damaging potential
`
`than the commercially available hydroxypropyl derivatives at
`
`concentrations typically used to solubilize pharmaceutical formulations. The range of
`
`concentrations depicted in the figure includes the concentrations typically used to
`
`solubilize pharmaceutical formulations when initially diluted in the blood stream after
`
`injection. After oral administration, SAE-CD does not undergo significant systemic
`
`absorption.
`
`The osmolality of a formulation is generally associated with its hemolytic
`
`10
`
`potential:
`
`the higher the osmolality (or the more hypertonic), the greater the hemolytic
`
`potential. Zannou et al. (“Osmotic properties of sulfobutyl ether and hydroxypropyl
`
`cyclodextrins’, Pharma. Res.
`
`(2001), 18(8), 1226-1231) compared the osmolality of
`
`solutions containing SBE-CD and HP-CD. Asdepicted in FIG. 2, the SBE-CD containing
`
`solutions have a greater osmolality than HP-CD containing solutions comprising similar
`
`15
`
`concentrations of cyclodextrin derivative. Thus, it is surprising that SAE-CD exhibits
`
`lower hemolysis than does HP-CD at equivalent concentrations, even though HP-CD has a
`
`lower osmolality.
`
`Methylated cyclodextrins have been prepared and their hemolytic effect on human
`
`erythrocytes has been evaluated. These cyclodextrins were found to cause moderate to
`severe hemolysis (Jodal et al., Proc. 4” Int. Symp. Cyclodextrins, (1988), 421-425;
`
`20
`
`Yoshidaet al., dnt. J. Pharm., (1988), 46(3), 217-222).
`
`Administration of cyclodextrins into the lungs of a mammal maynot be acceptable.
`
`In fact, literature exists on the potential or observed toxicity of native cyclodextrins and
`
`cyclodextrin derivatives. The NTP Chemical Repository indicates that o-cyclodextrin
`
`25
`
`may be harmful by inhalation. Nimbalkar et al. (Biotechnol. Appl. Biochem. (2001), 33,
`
`123-125) cautions on the pulmonary use of an HP-B-CD/diacetyldapsone complex due to
`
`its initial effect of delaying cell growth of lung cells.
`
`Even so, a numberof studies regarding the use of cyclodextrins for inhalation have
`
`been reported although none have been commercialized. The studies suggest that different
`
`30
`
`drug-cyclodextrin combinations will be required for specific optimal or even useful
`
`inhaled or intra-nasal formulations. Attempts have been made to develop cyclodextrin-
`
`containing powders andsolutions for buccal, pulmonary and/or nasal delivery.
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`U.S. Patent No. 5,914,122 to Otterbeck et al. discloses the preparation of stable
`
`budesonide-containing solutions for rectal administration as a foam. They demonstrate the
`
`use of cyclodextrin, such as B-CD, y-CD or HP-B-CD, and/or EDTAasa stabilizer.
`
`Cyclodextrin is also suggested as a solubilizer for increasing the concentration of
`
`budesonide in solution.
`
`In each case, the greatest shelf-life they report for any of their
`
`formulations is, in terms of acceptable retention of the active ingredient, only three to six
`
`months.
`
`U.S. Pregrant Patent Publication No. 20020055496 to McCoy et al. discloses
`
`essentially non-aqueous intra-oral formulations containing HP-B-CD. The formulations
`
`10
`
`may be administered with an aerosol, spray pumpor propellant.
`
`Russian Patent No. 2180217 to Chuchalin discloses a stable budesonide-containing
`
`solution for
`
`inhalation.
`
`The
`
`solution comprises budesonide, propylene glycol,
`
`poly(ethylene oxide), succinic acid, Trilon B, nipazole, thiourea, water, and optionally
`
`HP-B-CD.
`
`15
`
`Miiller et al. (Proceed. Int’l. Symp. Control. Rel. Bioact. Mater. (1997), 24, 69-70)
`
`discloses the results of a study on the preparation of budesonide microparticles by an
`
`ASES(Aerosol S