(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`25 March 2004 (25.03.2004)
`
`(10) International Publication Number
`
`WO 2004/024126 A1
`
`(51) International Patent Classifi(‘ation7: AGIK 9/48, 9/52
`
`(21) International Application Number:
`PCT/US2003/030960
`
`(22) International Filing Date:
`12 September 2003 (12.09.2003)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/410,850
`
`13 September 2002 (13.09.2002)
`
`US
`
`(71) Applicant (for all designated States except US): CYDEX,
`INC. [US/US]; 12980 Metcalf Avenue, Suite 470, Over-
`land Park, KS 66213 (US).
`
`(72) Inventors; and
`THOMPSON,
`(75) Inventors/Applicants (for US only):
`Diane, O. [US/US]; 13322 W. 113th, Overland Park, KS
`66210 (US). ZIMIVIERER, Rupert, O. [US/US]; 1162
`North 1100 Rd., Lawrence, KS 66047 (US). PIPKIN,
`James, D. [US/US]; 4500 Woodland Dr., Lawrence, KS
`66049 (US).
`
`(74) Agent: l\IATOS, Rick; Innovar, L.L.C., P.O. Box 250647,
`Plano, TX 75025-0647 (US).
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, ES. FI, GB, GD, GE, GH,
`GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC,
`LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
`MX, MZ, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC,
`SD, SE, SG, SK, SL, SY, TJ, TM, TN, TR, TT, T7,, UA,
`UG, US, UZ, VC, VN, YU, ZA, ZM, ZW.
`
`Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD. SL, SZ, TZ, UG. ZM, ZW),
`Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`ES, FI, FR, GB, GR, HU, IE, IT, LU, MC, NL, PT, RO,
`SE, SI, SK, TR), OAPI patent (BF, BJ, CF, CG, CI, CM,
`GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`with international search report
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`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.
`
`!—
`
`<11
`
`(54) Title: CAPSULES CONTAINING AQUEOUS FILL COMPOSITIONS STABILIZED WITH DERIVATIZED CYCLODEX—
`TRIN
`
`\D
`
`NV
`
`-1
`<1-
`
`NcR <
`
`-
`(57) Abstract: A capsule containing an aqueous fill composition that comprises water, a derivatized cyclodextrin, such as sulfoalkyl
`2 ether cyclodextrin (SAE—CD) or hydroxypropyl cyclodextrin (HPCD), optionally one or more active agents and optionally one or
`more excipients is stabilized from degradation, erosion, swelling or dissolution of its shell during storage. The derivatized eyclodex—
`trin is present in an amount sufficient to reduce, eliminate or inhibit degradation, erosion, swelling and/or dissolution of the shell
`0 by water present in the fill composition. Alternatively, the derivatized cyclodextrin and another shel1—stabilizing material together
`stabilize the shell from degradation, erosion, swelling and/or dissolution by water present in the fill composition. The derivatized
`B
`cyclodextrin can reduce the water activity of the fill composition.
`
`APOTEX EX1034
`
`Page 1
`
`

`
`WO 2004/024126
`
`PCT/US2003/030960
`
`Capsules Containing Aqueous Fill Compositions Stabilized with
`Derivatized Cyclodextrin
`
`By:
`
`Diane 0. Thompson, James D. Pipkin, Rupert O. Zimmerer
`
`FIELD OF THE INVENTION
`The present invention relates to a capsule containing a derivatized cyclodextrin in
`
`an aqueous fill, wherein the cyclodextrin is present in an amount sufficient to stabilize the
`
`shell of the capsule from erosion, dissolution, swelling or degradation by water in the fill.
`
`BACKGROUND OF THE INVENTION
`
`Liquid, or semi-solid filled capsules are widely known. These fill compositions
`
`are generally preferred over solid filled capsules, since it is easier to obtain a higher
`
`content uniformity for liquid or semi-solid filled capsules than it is for solid filled
`
`capsules.
`
`Capsule fill compositions can be aqueous or non-aqueous. Materials generally
`
`used for capsule fill compositions include: 1) water-immiscible, volatile and nonvolatile
`
`liquids, 2) water miscible, volatile and nonvolatile liquids, and 3) miscellaneous carriers
`
`such as glycerin, propylene glycol, water, and low—molecular weight alcohols, ketones,
`
`acids, amines, and esters. Suspensions of the active are often included in vegetable or
`
`mineral oils, triglycerides, glycols such as polyethylene glycols and propylene glycol,
`
`surfactants such as polysorbates, or combinations of these.
`
`The shell-forming material ofthe capsule is chosen so as to maximize the stability -
`
`of the shell toward the fill composition, while at the same time maintaining the desired
`
`release profile for the active agent. Non-aqueous fill compositions are used widely
`
`because the shell of a capsule must be water soluble, erodible or degradable in order to be
`
`usefiil for use in an aqueous environment, e.g., for oral administration to a subject. Quite
`
`often, however, it is desirable to include water in the fill composition in order to obtain
`
`the desired active agent release profile, increase dissolution of active agent in the fill
`
`composition and/or maximize stability of the ingredients in the fill composition. When
`
`an aqueous fill composition is used, the shell of the capsule is generally made of material
`
`that is more resistant to water dissolution, erosion or degradation.
`
`Page 2
`
`Page 2
`
`

`
`WO 2004/024126
`
`PCT/US2003/030960
`
`-2-
`
`A number of different relatively water stable shell compositions are known.
`
`Those shell compositions generally include materials or are made by processes that
`
`reduce the instability of the shell toward water in the fill composition. For example,
`
`Banner Pharmacaps and Cardinal Health provide capsules that are somewhat stabilized
`
`for a lipophilic fill and other for a hydrophilic fill. However, using such a shell results in
`
`altered performance of the capsule formulation. Accordingly,
`
`the pharmaceutical
`
`scientist must carefully balance the amount of water included in the fill composition
`
`against the aqueous stability properties of the shell. Moreover, the known aqueous fill
`
`compositions are limited in the amounts of water and the combination of active agents
`
`and excipients that can be included therein.
`
`In other words, known shells containing fill
`
`compositions with high amounts of water still degrade, dissolve, swell or erode during
`
`storage.
`
`A number of references disclose capsule dosage forms filled with an aqueous
`
`liquid or semi-solid vehicle, an active agent, and another component added to reduce or
`
`stop dissolution, erosion or degradation of the shell by the fill composition.
`
`Kuentz et al. (International Journal ofPharmaceutics (2002), 236(l—2), 145-152)
`
`filled with a liquid composition comprising water, PEG and
`disclose capsules
`poly(vinylpyrrolidone) or comprising water, glycerides (LABRASOL®) and colloidal
`silicon dioxide (AEROSIL®).
`The components were added to determine which
`
`combination thereof would be able to reduce or stop dissolution, erosion or degradation
`
`ofthe shell by the fill composition. Kuentz et al. do not disclose the use of cyclodextrins.
`
`Bowtle
`
`(Presentation entitled “Liquid—encapsulation
`
`technology for oral
`
`delivery”) discloses the use of hydrogenated glucose syrup as a material suitable for use
`
`in liquid-filled capsules. Bowtle does not disclose the use of cyclodextrins to reduce or
`
`stop dissolution, erosion or degradation of the shell by the fill composition.
`
`Japanese Patent No. JP 61207329 to Mochizuki et al. discloses a soft gelatin
`
`capsule filled with an aqueous liquid vehicle, a sugar and an active agent. The sugar is
`
`present in amounts of 2 55% wt. with respect to the fill composition. Sugars such as
`
`sucrose, glucose, fructose, and maltose are disclosed. The sugar is present in an amount
`
`sufficient to reduce or stop dissolution, erosion or degradation of the shell by the fill
`
`Page 3
`
`Page 3
`
`

`
`WO 2004/024126
`
`PCT/US2003/030960
`
`-3-
`
`composition. Mochizuki et al. do not disclose the use of cyclodextrins to reduce or stop
`
`dissolution, erosion or degradation of the shell by the fill composition.
`
`German Patent No. DE 19545043 to Lucks et al. discloses a liquid-filled soft
`
`gelatin capsule. The liquid is present in a single phase. The fill composition comprises
`1-20% wt. polyol (such as glycerol, propanediol or PEG) or benzyl alcohol, l-20% wt.
`
`surfactant, 79-98% wt. co-surfactant (such as glycerides), <5% wt. ethanol and <l0% wt.
`
`water. Lucks et al. do not disclose cyclodextrins. Water is present in an amount low
`
`enough to minimize dissolution, erosion or degradation of the shell by the fill
`
`composition. Lucks et al. do not disclose the use of cyclodextrins to reduce or stop
`
`dissolution, erosion or degradation of the shell by the fill composition.
`
`U.S. Patent No. 5,037,698 to Brunel discloses a solid or semi-solid filled capsule
`
`wherein the fill composition comprises water (0.l—10% wt.), a thickening agent (235%
`
`wt.), a hygroscopic or deliquescent agent (0.1-50% wt.) and optionally an equilibrium
`protecting agent (0.1-15% wt.). The water is present at or near stoichiometric amounts
`with respect to the hygroscopic or deliquescent agent so that a hydrate can form but
`degradation of the shell by water
`is minimized.
`The thickening agent
`is a
`thermosoftening solid or semi-solid excipient. The equilibrium protecting agent includes
`
`compounds such as aliphatic or aromatic hydroxy compounds including for example
`
`demulcents (glycerin) and oils. Brunel does not disclose the use of cyclodextrins.
`
`U.S. Patent No. 5,707,648 to Yiv discloses a biphasic liquid-filled capsule
`
`containing an oil phase and an aqueous phase. The aqueous phase includes water (2—30%
`
`wt.) and PEG (60-95% wt.), wherein the ratio of PEG to water is 22:1 or 2:1-99:1. The
`
`formulation also requires a surfactant and an active agent. The PEG is present in an
`
`amount sufficient to reduce or stop dissolution, erosion or degradation of the shell by the
`
`fill composition. Yiv does not disclose the use of cyclodextrins.
`
`U.S. Patent Pregrant Publication No. 2003/0133974 to Curatolo et al. discloses an
`
`encapsulated dosage form containing sertraline; however, that dosage form comprises a
`
`water immiscible carrier medium.
`
`Cyclodextrins and their derivatives are widely used in liquid formulations to
`
`enhance the aqueous solubility of hydrophobic compounds. Cyclodextrins are cyclic
`
`Page 4
`
`Page 4
`
`

`
`WO 2004/024126
`
`PCT/US2003/030960
`
`-4-
`
`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 on-, 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 exterior surfaces and
`hydrophobic interior cavities. In aqueous solutions, these hydrophobic cavities provide a
`haven for hydrophobic organic compounds, which can fit 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 involve the formation of any
`
`covalent bonds.
`
`Chemical modification of the parent cyclodextrins (usually at the hydroxyl
`
`moieties) has resulted in derivatives with sometimes improved safety while retaining or
`
`improving the complexation ability of the cyclodextrin. A number of different
`cyclodextrin derivatives are currently available including sulfobutyl ether derivatives
`
`such as SBE1-B-CD and SBE4—|3-CD (degree of substitution~4), SBE7-[3-CD (degree of
`
`substitution~7; CAPTISOL® cyclodextrin);
`
`hydroxypropyl
`
`derivatives
`
`such
`
`as
`
`ENCAPSINTM (degree of substitution~4; HP4-B-CD) and MOLECUSOLTM (degree of
`
`substitution~8;
`
`I-[P8-B—CD); i carboxylated derivatives; sulfated derivatives; alkylated
`
`derivatives; hydroxyalkylated derivatives; methylated derivatives; and carboxy-[3-
`
`cyclodextrins, e.g. succinyl-[3-cyclodextrin, 6A-amino-6A-deoxy-N-(3-carboxypropyl)-[3-
`
`cyclodextrin.
`
`The SAE-CDs are a class of negatively charged cyclodextrins, which vary in the
`
`nature of the alkyl spacer, the salt form, the degree of substitution and the starting parent
`
`cyclodextrin. The sodium salt of the sulfobutyl ether derivative of beta-cyclodextrin,
`
`with an average of about 7 substituents per cyclodextrin molecule (SBE7-[3-CD), is being
`commercialized by CyDex, Inc. (Kansas) as CAPTISOL® cyclodextrin.
`
`Page 5
`
`Page 5
`
`

`
`WO 2004/024126
`
`PCT/US2003/030960
`
`
`
`RH:-I-I};;_,, or { »{tL‘I~3l;g}:.¢3ii)3§%l‘a{iI,,
`where z1=fi.{3-"M
`
`$u§f0butylE:§tl§et~fii~€S;¢e§ad:-amine rgrzaptisafi
`
`The anionic sulfobutyl ether substituent dramatically improves the aqueous
`
`solubility of the parent cyclodextrin. Reversible, non-covalent, complexation of drugs
`with the CAPTISOL® cyclodextrin generally allows for increased solubility and stability
`
`of drugs in aqueous solutions.
`
`A number of references disclose capsule dosage forms comprising a fill
`
`composition comprising a cyclodextrin, aqueous or non-aqueous vehicle, active agent and
`
`other pharmaceutical excipients.
`
`U.S. Patents No. 6,287,594 to Wilson et al. and No. 6,365,180 to Meyer et al.
`
`disclose oral liquid compositions that can be included in capsule dosage forms. The
`
`liquid compositions comprise an acidic active agent, a dispersing agent, a solubilizing
`agent
`(0—90% or 60-90% wt.), an optional surfactant (0-10% wt.) and an optional
`
`plasticizing agent (0-25% wt.). The dispersing agent can be a carbohydrate-based agent,
`for example a “derivatized cyclodextrin”.
`The solubilizing agent
`is water or
`
`poly(ethylene glycol). The ratio of active agent to dispersing agent is about 3:1 to about
`
`1:30. The patents do not disclose that the cyclodextrin can reduce or stop dissolution,
`
`erosion or degradation of the shell by the aqueous fill composition. Moreover, no
`
`examples including a cyclodextrin are disclosed.
`
`U.S. Patent No. 6,383,471 to Chen et al. discloses a liquid composition
`
`comprising an ionizable hydrophobic active agent,
`
`ionizing agent, surfactant and
`
`Page 6
`
`Page 6
`
`

`
`WO 2004/024126
`
`PCT/US2003/030960
`
`-6-
`
`optionally solubilizers, triglycerides and neutralizing agents. The liquid composition can
`be used in capsules. Chen et al. disclose that solubilizers can include cyclodextrins,
`
`among many other compounds. A sulfobutyl ether cyclodextrin is listed as an exemplary
`
`cyclodextrin. Chen et al. do not disclose or suggest that the cyclodextrin is present in an
`amount sufficient to reduce or stop dissolution, erosion or degradation of the shell by the
`
`aqueous fill composition.
`
`'
`
`U.S. Patents No. 6,046,177 and No. 5,874,418 to Stella et al. disclose capsule
`
`dosage forms containing a non-aqueous solid physical mixture of an SAE-CD and an
`active agent. The physical mixture is not a liquid or semi—solid composition and water is
`not included in the physical mixture in order to reduce the formation of an inclusion
`
`complex between the cyclodextrin and the active agent. Stella et al. do not disclose that
`
`the cyclodextrin can be present in an amount sufficient to reduce or stop dissolution,
`
`erosion or degradation of the shell by water in the fill composition.
`
`U.S. Patents No. 5,376,645 and No. 5,134,127 to Stella et al. disclose
`
`pharmaceutical compositions comprising an active agent, an SAE-CD and a liquid or
`solid carrier. The SAE-CD and active agent are present as an inclusion complex. Stella
`
`et al. generally disclose “soft gelatin capsules wherein the active ingredient (the mixture
`
`containing the inclusion complex of SAE-CD and active agent) is mixed with water or
`
`oil”.
`
`They also disclose that, “Pharmaceutical
`
`formulations
`
`suitable for oral
`
`administration wherein the carrier is liquid may conveniently be presented as a solution
`
`in an aqueous liquid or a non-aqueous liquid, or as an oil-in-water or water-in-oil liquid
`
`emulsion.” Stella et al. do not disclose or suggest that an SAE-CD can be present in an
`
`aqueous fill composition (for capsules)
`
`in an amount sufficient
`
`to reduce or stop
`
`dissolution, erosion or degradation of the shell by water in the fill composition.
`
`Moreover, Stella et al. disclose combinations wherein the SAE-CD must form an
`
`inclusion complex with the active agent.
`
`U.S. Patent No. 3,426,011 to Parmerter et al. discloses anionic cyclodextrin
`
`derivatives having sulfoalkyl ether substituents. Parmerter et al. do not disclose the use
`
`of sulfoalkyl ether cyclodextrins in an aqueous composition contained within a capsule.
`
`Lammers et al. (Recl. Trav. Chim. Pays-Bas (1972), 91(6), 733-742); Staerke (1971),
`
`Page 7
`
`Page 7
`
`

`
`WO 2004/024126
`
`PCT/US2003/030960
`
`-7-
`
`23(5), 167-71) disclose sulfoalkyl ether derivatized cyclodextrins; however, they do not
`disclose the use of cyclodextrins to reduce or stop dissolution, erosion or degradation of a
`
`shell by an aqueous fill composition.
`A need remains for improved capsule fill compositions that stabilize a shell from
`
`dissolution, erosion, swelling or degradation by water in the fill composition. None of
`
`the art discloses or suggests the invention as claimed herein. The prior art does not
`
`disclose an aqueous fill composition for a capsule, wherein the fill composition
`comprises a derivatized cyclodextrin, such as an SAE—CD, an active agent, and an
`aqueous carrier, and the derivatized cyclodextrin is present in an amount sufficient to
`reduce or stop dissolution, erosion, swelling or degradation of the capsule shell by water
`in the fill composition. Moreover, the prior art does not disclose or suggest a method of
`stabilizing a water soluble, erodible, swellable or degradable capsule shell surrounding an
`aqueous fill composition by including a derivatized cyclodextrin in the fill composition.
`
`SUMMARY OF THE INVENTION
`The present invention seeks to overcome some or all ofthe disadvantages inherent
`in other known formulations. The invention provides a commercially viable composition
`
`for use in hard or soft capsules, such that capsules filled with the aqueous fill composition
`
`can be prepared and stored without significant degradation, erosion, swelling or
`dissolution of the capsule shell during the acceptable shelf—life of the filled capsule. The
`
`invention provides a capsule dosage form and an aqueous fill composition therefor. The
`capsule comprises a soft or hard shell. In one aspect, the invention provides a sulfoalkyl
`ether cyclodextrin (SAE-CD)-based (derivatized cyclodextrin-based)
`aqueous
`fill
`composition. The fill composition comprises an aqueous vehicle, a sulfoalkyl ether
`cyclodextrin (SAE-CD), an active agent, and optionally other ingredients. The shell is
`generally made from water soluble, erodible, swellable or degradable material(s);
`however, a shell material that is not water soluble, erodible, swellable or degradable can
`
`also be used. The SAE—CD, or other derivatized cyclodextrin, is present in an amount
`
`sufficient to reduce or stop dissolution, erosion, swelling or degradation of the shell by
`
`water in the fill composition.
`
`In other words, the derivatized cyclodextrin reduces
`
`dissolution, erosion, swelling or degradation of the shell by the fill composition as
`
`compared to a similar fill composition excluding the derivatized cyclodextrin,
`
`i.e.,
`
`Page 8
`
`Page 8
`
`

`
`WO 2004/024126
`
`PCT/US2003/030960
`
`-3-
`
`wherein the derivatized cyclodextrin is replaced by water or another non-shell-stabilizing
`
`material.
`
`In the absence of other shell-stabilizing material(s), the SAE-CD stabilizes the
`
`capsule shell against dissolution, erosion, swelling or degradation caused by water in the
`
`fill composition.
`The capsule dosage form comprises a shell and an aqueous fill composition
`comprising an SAE-CD, or water soluble derivatized cyclodextrin.
`In the absence of
`other shell-stabilizing materials and depending upon the materials that comprise the shell,
`
`the fill composition can include at least about 30% by weight of SAE-CD, or derivatized
`cyclodextrin, based upon the total weight of water and SAE-CD, or derivatized
`cyclodextrin, present. The amount of derivatized cyclodextrin required to provide the
`desired level of shell stabilization will vary according to the composition of the shell and
`
`the materials comprising the fill composition. The more stable a shell is toward water,
`
`the lower the amount of derivatized cyclodextrin that may be required. The less stable
`
`the shell is toward water, the greater the amount of derivatized cyclodextrin that may be
`
`the fill composition
`In the absence of other shell-stabilizing materials,
`required.
`comprises less than about 70% by weight of water based upon the total weight of water
`
`and SAE-CD present. The minimum shelf life of the filled capsule is at least about 1
`
`week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, or 1 year, or more than about 1
`
`year.
`
`The invention also provides a method of stabilizing a water soluble, erodible or
`
`degradable capsule shell
`
`surrounding an aqueous fill composition.
`
`The method
`
`comprises the step of including an SAE-CD, or derivatized cyclodextrin,
`
`in the fill
`
`composition such that the SAE-CD, or derivatized cyclodextrin, is present in an amount
`
`sufficient to reduce or stop the dissolution, erosion, swelling or degradation of the
`
`capsule shell caused by the water in the fill composition.
`
`The fill composition can include other shell-stabilizing materials and/or other
`
`water activity-reducing materials if desired. The fill composition can also include other
`
`ingredients suitable for use in capsule fill compositions.
`
`It
`
`is not necessary for the active agent
`
`to complex with the derivatized
`
`cyclodextrin in order for the derivatized cyclodextrin to exert its stabilizing effect upon
`
`Page 9
`
`Page 9
`
`

`
`WO 2004/024126
`
`PCT/US2003/030960
`
`-9-
`
`the capsule shell. The fill composition can include one or more active agents, and each
`active agent independently may or may not complex with the derivatized cyclodextrin.
`Any shell forming material suitable for use in hard or soft shell capsules or the
`
`encapsulation of fill composition can be used in the present invention.
`The SAE-CD formulation has a sufficiently high stability for use as a commercial
`
`product. The formulation can be prepared as a clear aqueous composition that is
`sterilizable by sterile filtration (for example, filter pore size of less than or equal to 0.22
`
`um) and other conventional methods. The aqueous composition is stable under a variety
`of storage conditions. The SAE-CD can be used to enhance the solubility of active agents
`by non-covalent ionic binding and/or by complexation via the formation of inclusion
`
`complexes.
`The fill composition may or may not be clear depending upon the identity and
`
`amounts of ingredients included therein. During storage the clarity of the fill
`
`In other words, one or more components of the fill
`composition may or may not change.
`composition may further dissolve or precipitate during storage. The fill composition,
`which is a water-containing composition, can be a gel, syrup, fluid, semi-solid, solid,
`
`suspension, emulsion, paste, or glassy material.
`
`Accordingly, one aspect of the invention provides an aqueous fill composition in
`
`a water erodible, degradable, swellable or soluble shell (or encapsulating material), the
`
`fill composition comprising water, one or more derivatized cyclodextrins, optionally one
`
`or more active agents and optionally one or more excipients, wherein the derivatized
`
`cyclodextrin is present in an amount sufficient to reduce or stop the erosion, degradation,
`
`swelling or dissolution of the shell by the fill composition.
`
`Specific embodiments of the invention include those wherein: 1) the derivatized
`
`cyclodextrin is SAE-CD and is present in an amount of at least about 30% by wt. based
`
`upon the total weight of water and SAE-CD; 2) the fill composition further comprises a
`
`shell-stabilizing material; 3) the fill composition has a pH in the range of about 1-1 1; 4)
`
`the fill composition comprises one or more excipients; 5) the shell is a soft shell; 6) the
`
`shell is a hard shell; 7) the water activity of the fill composition is less than about 0.95 as
`
`measured according to the procedures detailed herein; 8) the fill composition further
`
`Page 10
`
`Page 10
`
`

`
`WO 2004/024126
`
`PCT/US2003/030960
`
`-10-
`
`comprises a solubility-enhancing agent; 9) the SAE-CD complexes with one or more of
`the active agents; 10) the SAE-CD does not complex with the one or more active agents;
`11) the fill composition further comprises a liquid carrier other than water; 12) the fill
`composition is a liquid; 13) the fill composition is a semi-solid; 14) the fill composition is
`
`a solid; 15) the fill composition has been 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; 16) the formulation
`
`has been prepared at a temperature approximating ambient temperature; 17) the SAE-CD,
`or derivatized cyclodextrin, reduces the water activity of the aqueous fill composition;
`
`l8) the shell is a hard gelatin shell and the fill composition comprises at least 60% wt. of
`derivatized cyclodextrin; 19) the shell is a soft gelatin shell and the fill composition
`
`comprises at least 50% wt. of derivatized cyclodextrin; 20) the shell is a hard shell
`comprising cellulose, cellulose derivative, starch, starch derivative, or a combination
`thereof and optionally other excipients, and the fill composition comprises at least 30%
`
`wt. of derivatized cyclodextrin; and/or 21) the fill composition further comprises a water
`
`activity-reducing material.
`
`The invention also provides a first capsule within a second capsule.
`
`In this case
`
`the first and/or second capsule can contain the aqueous fill composition.
`
`Another aspect of the invention provides a method of stabilizing an aqueous
`
`composition—filled capsule from erosion, dissolution, swelling or degradation of its shell by
`
`water present in the fill, the method comprising the step of including in the aqueous fill a
`
`derivatized cyclodextrin present in an amount sufficient to reduce or stop the rate of erosion,
`
`dissolution, swelling or degradation ofthe shell by water in the fill composition as compared
`
`to the rate of erosion, dissolution, swelling or degradation of the shell by a similar fill
`
`composition excluding the derivatized cyclodextrin,
`
`i.e., a fill composition wherein the
`
`derivatized cyclodextrin is replaced by water or another material that does not stabilize the
`
`shell (a non-shell-stabilizing material). The derivatized cyclodextrin is capable of stabilizing
`
`the shell against erosion, dissolution, swelling or degradation of the shell by water in the fill
`
`composition either in the absence, and optionally presence, of another shell-stabilizing
`
`material.
`
`Page 1 1
`
`Page 11
`
`

`
`WO 2004/024126
`
`PCT/US2003/030960
`
`-11-
`
`Yet another aspect of the invention provides an aqueous fill composition enclosed
`
`within an encapsulating material, the fill composition comprising a derivatized cyclodextrin
`
`and an aqueous carrier, wherein the derivatized cyclodextrin is present in an amount
`sufficient to reduce the water activity of the fill composition thereby reducing the rate of
`
`erosion, dissolution, swelling or degradation of the encapsulating material by water in the
`
`aqueous fill. The water activity of the fill composition is generally reduced to less than
`
`about O.95i0.025, less than 0.95i0.01, less than 0.925, or less than 0.90. The preferred
`
`water activity value may vary according to the components present in the fill and according
`to the composition of the capsule shell itself. The observed water activity value can also
`vary according to the instrument used to measure it as well as the calibration of the
`instrument and reproducibility of measurements (as expressed by standard deviation) taken
`
`by the instrument. The preferred water activity value will also vary according to the
`composition of the shell. Generally, the more water stable the shell, the higher the water
`
`activity of the fill composition can be, and the less water stable the shell, the lower the water
`activity of the fill composition should be, if the fill composition does not contain any other
`
`shell-stabilizing material(s).
`1) the derivatized
`Specific embodiments of the invention include those wherein:
`cyclodextrin is SAE-CD, HPCD, a water soluble derivatized cyclodextrin capable of
`reducing the water activity of the fill composition or a mixture thereof; 2) the fill
`
`composition further comprises a shell-stabilizing material; 3) the fill composition further
`
`comprises a water activity-reducing agent; 4) the fill composition further comprises an
`active agent; and/or 5) the fill composition further comprises one or more pharmaceutical
`
`excipients.
`
`The invention also provides a method of reducing the water activity of an aqueous
`
`composition, the method comprising the step of including a water soluble derivatized
`cyclodextrin in the aqueous composition at a concentration sufficient to reduce the water
`
`activity.
`
`The invention also provides capsule formulations that provide active agent release
`
`according to a controlled, sustained, extended, slow, rapid, pulsed,
`
`timed,
`
`targeted,
`
`colonic, zero order, pseudo-zero order, first order, pseudo-first order, and/or enteric
`
`Page 12
`
`Page 12
`
`

`
`WO 2004/024126
`
`PCT/US2003/030960
`
`-12-
`
`release profile, wherein release of the active agent begins immediately (less than 30
`
`minutes) or after passage of a delay period (2 30 min) afier exposure to an environment
`
`of use.
`
`In other words, initial release of drug can be immediate or delayed as well as
`
`being released according to the modified release profiles mentioned herein. The capsule
`formulation can be a coated capsule, uncoated capsule, osmotic capsule, capsule within a
`
`capsule, or multi-layered capsule.
`
`The invention also provides a capsule comprising:
`
`a water soluble, erodible, degradable and/or swellable shell; and
`
`an aqueous fill composition comprising water present in an amount sufficient to
`
`solubilize, erode, degrade and/or swell the shell, one or more active agents, and a water
`
`soluble cyclodextrin derivative present in an amount sufficient to suppress dissolution,
`erosion, degradation or swelling of the shell by water in the fill composition, wherein the
`capsule has a shelf-life of at least one week.
`.
`Another embodiment of the invention provides a stabilized capsule formulation
`
`having a shelf-life of at least one week, the formulation comprising:
`
`a water soluble, erodible, swellable and/or degradable shell, and
`
`an aqueous fill composition comprising a water soluble cyclodextrin derivative,
`
`the capsule
`an aqueous carrier and optionally one or more active agents; wherein,
`formulation has an increased shelf life as compared to a similar capsule formulation
`
`excluding the cyclodextrin derivative and any other shell-stabilizing material; water in
`
`the aqueous carrier is present in an amount sufficient to at least partially dissolve, erode,
`
`swell and/or degrade the shell; and the cyclodextrin derivative is present in an amount
`
`sufficient to reduce the rate of or eliminate dissolution, erosion, swelling or degradation
`
`of the shell by water in aqueous carrier.
`
`Still another embodiment of the invention provides
`
`An aqueous fill composition enclosed within a water soluble, erodible, swellable
`
`and/or degradable encapsulating material, the fill composition comprising:
`
`an aqueous carrier present in an amount sufficient to at least partially dissolve,
`
`erode, swell and/or degrade the encapsulating material;
`
`Page 13
`
`Page 13
`
`

`
`WO 2004/024126
`
`PCT/US2003/030960
`
`-13-
`
`a water soluble cyclodextrin derivative present in an amount insufficient to on its
`
`own stop dissolution, erosion, swelling and/or degradation of the encapsulating material
`
`by the aqueous carrier;
`
`a shell-stabilizing material present in an amount insufficient to on its own stop
`
`dissolution, erosion, swelling and/or degradation of the encapsulating material by the
`
`aqueous carrier;
`
`optionally, one or more active agents; and
`
`optionally, one or more excipients; wherein,
`
`the cyclodextrin derivative and the shell-stabilizing material synergistically at
`least reduce the rate of or stop dissolution, erosion, swelling and/or degradation of the
`
`encapsulating material by the aqueous carrier.
`In specific emb