(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`14 October 2004 (14.10.2004)
`
`
`
`PCT
`
`ND NM AAA
`
`(10) International Publication Number
`WO 2004/087101 A2
`
`(51) International Patent Classification’:
`
`A61K 9/00
`
`(74)
`
`(21) International Application Number:
`PCT/US2004/009387
`
`Agents: STEPNO, Norman,H. et al.; BURNS, DOANE,
`SWECKER & MATHIS, LLP, PO BOX 1404, Alexandria,
`VA 22313-01404 (US).
`
`(22) International Filing Date:
`
`26 March 2004 (26.03.2004)
`
`(81)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`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, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KP, KR, K7%, LC, LK, LR, LS, LT, LU, LV, MA, MD,
`MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
`PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
`TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
`ZW.
`
`US
`US
`US
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARTPO (BW, GI,
`GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
`Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), Euro-
`pean (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR,
`GB, GR, HU, IE, IT, LU, MC, NL, PL, PT, RO, SE, SI, SK,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`ML, MR, NE, SN, TD, TG).
`
`[Continued on next page]
`
`(30) Priority Data:
`60/458,922
`60/484,756
`60/541 ,247
`
`28 March 2003 (28.03.2003)
`2 July 2003 (02.07.2003)
`4 February 2004 (04.02.2004)
`
`(71) Applicant (for all designated States except US): IVAX
`CORPORATION [US/US]; 4400 Biscayne Boulevard,
`Miami, Florida 33137 (US).
`
`(72)
`(75)
`
`Inventors; and
`Inventors/Applicants (for US only): BODOR, Nicholas,
`8. [US/US]; 10101 Collins Avenue, #4A, Bal Harbour,
`Florida 33154 (US). DANDIKER, Yogesh [GB/GB]; 17
`New Road, Digswell, Welwyn Garden City Herts AL6
`OAE (GB).
`
`(54) Title: ORAL FORMULATIONS OF CLADRIBINE
`
`
`
`(57) Abstract: ABSTRACT OF THE DISCLOSURE Provided are compositions ofcladribine and cyclodextrin which are especially
`
`
`
`
`
`
`
`Cladribine(M)conc.
`
`0.080 -
`
`0.070
`
`0.060
`
`0.050 -
`
`0.040 -
`
`0.030
`
`0.020 -
`
`0.010 J
`
`0.000 ~
`
`0.000
`
`0.050
`
`WO2004/087101A2[IMDTIMNIIIMINIAVIMIMINIMANAMITUCMUM suited for the oral administration of cladribine.
`
`
`~T
`
`——
`
`0.100
`
`0.150
`
`0.200
`
`0.250
`
`0.300
`
`CD conc.(M)
`
`Hopewell EX1022
`
`Hopewell EX1022
`
`1
`
`

`

`WO 2004/087101 A2
`
`_[IITITTINTAIMIININMTIAMATACTTA MTA
`
`Published:
`— without international search report and to be republished
`uponreceipt ofthat report
`
`Far 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.
`
`2
`
`

`

`WO 2004/087101
`
`PCT/US2004/009387
`
`As
`
`ORAL FORMULATIONS OF CLADRIBINE
`
`FIELD OF THE INVENTION
`
`The invention relates to a composition comprising a complex
`
`5
`
`cladribine-cyclodextrin complex formulated into a solid oral dosage form and
`
`to a method for enhancingthe oral bioavailability of cladribine.
`
`BACKGROUND OF THE INVENTION
`
`Cladribine, which is an acid-labile drug, has the chemical structure as
`
`10
`
`set forth below:
`
`OH
`
`It is also known as 2-chloro-2'-deoxyadenosine or 2-CdA. Cladribine exists
`
`as a white, nonhydroscopic, crystalline powder, consisting of individual
`
`crystals and of crystalline aggregates.
`
`15
`
`Cladribine is an antimetabolite which has use in the treatment of
`
`lymphoproliferative disorders.
`
`It has been usedto treat experimental
`
`leukemias such as L1210 andclinically for hairy cell leukemia and chronic
`
`lymphocytic leukemia as well as Waldenstrom’s macroglobulinaemia.
`
`It has
`
`3
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`

`

`WO 2004/087101
`
`PCT/US2004/009387
`
`Be
`
`also been used as an immunosuppressive agent and as a modality for the
`
`treatment of @ variety of autoimmune conditions including rheumatoid
`
`arthritis, inflammatory bowel disease (e.g., Crohn’s disease, ulcerative
`
`colitis) and multiple sclerosis (see e.g., J. Liliemark, Clin. Parmacokinet,
`
`It has also been investigated, either experimentally
`32(2): 120-131, 1997).
`or clinically in, for example, lymphomas, Langerhan’s cell histiocytosis, lupus
`
`erythematosus, chronic plaque psoriasis, Sezary syndrome, Bing-Neel
`
`syndrome, recurrent glioma, and solid tumors.
`
`Oral delivery of drugsis often preferred to parenteral delivery for a
`
`10
`
`variety of reasons, foremost patient compliance, or for cost or therapeutic
`
`15
`
`20
`
`considerations. Patient compliance is enhancedinsofar as oral dosage
`
`formsalleviate repeated health care providervisits, or the discomfort of
`
`injections or prolongedinfusion times associated with someactive drugs. At
`a time of escalating health care costs, the reduced costs associated with oral
`administration versus parenteral administration costs gain importance. The
`
`cost of parenteral administration is much higher due to the requirementthat
`
`a health care professional administer the cladribine in the health care
`
`provider setting, which also includesall attendant costs associated with such
`administration. Furthermore, in certain instances, therapeutic considerations
`such as the need for a slow release of cladribine over a prolonged period of
`
`time maybe practically met only by oral or transmucosaldelivery.
`
`However, to date the oral delivery of cladribine has been plagued by
`low bioavailability (see, e.g., J. Liliemark et al., J. Clin. Oncol., 10(10): 1514-
`
`1518, 1992), and suboptimalinterpatient variation (see, e.g., J. Liliemark,
`
`25
`
`Clin. Pharmacokinet, 32 (2): 120-131, 1997). See also, A. Tarasuik,efal.
`
`reporting poor absorption and pH dependentlability (Arch. Immunol. et
`
`Therapiae Exper., 42: 13-15, 1994).
`
`Cyclodextrins are cyclic oligosaccharides composed of cyclic a-(1—-4)
`
`linked D-glucopyranose units. Cyclodextrins with six to eight units have
`
`4
`
`

`

`WO 2004/087101
`
`PCT/US2004/009387
`
`-3-
`
`been named o-, B- and y-cyclodextrin, respectively. The numberof units
`
`determines the size of the cone-shaped cavity which characterizes
`cyclodextrins and into which drugs may be included to form stable
`complexes. A numberofderivatives ofa-, B- and y-cyclodextrin are known
`in which one or more hydroxyl groups is/are replaced with ether groups or
`
`other radicals. These compounds are thus known complexing agents and
`
`have been previously used in the pharmaceutical field to form inclusion
`
`complexes with water-insoluble drugs andto thus solubilize them in aqueous
`
`media.
`
`10
`
`Recently, Schultz ef a/., in U.S. Patent No. 6,194,395 B1, have
`
`described complexing and solubilizing cladribine with cyclodextrin. The
`
`Schultz ef a/. patent primarily addresses the problemsinherentin previously
`
`described aqueous formulations of cladribine, particularly for subcutaneous
`
`and intramuscularinjection. Schultz ef a/. have found that cladribine is not
`
`15
`
`only significantly more soluble in aqueous media when formulated with
`
`cyclodextrin, but also is more stable against acid-catalyzed hydrolysis when
`
`combined with cyclodextrin. The latter finding is taught to be of particular
`
`benefit in the formulation of solid oral dosage forms, where the compound
`
`would normally undergo hydrolysis in the acid pH of the stomach contents.
`
`20
`
`Schultz ef a/. do not appear to have described any actual work in connection
`
`with solid oral dosage forms.
`
`In fact, they describe only one methodof
`
`preparing the solid dosage form, which is a melt extrusion process, in which
`
`the cladribine and cyclodextrin are mixed with other optional additives and
`
`then heated until melting occurs. Furthermore, the broad dosage rangesof
`
`25
`
`1 mg to 15 mg of cladribine and 100 mg to 500 mg of cyclodextrin listed in
`
`the patent suggest nocriticality to the particular amountof cyclodextrin to be
`
`present with a given amountof cladribine in a solid oral dosage form.
`
`Indeed, these dosage rangesinclude many combinations which may be
`
`suitable as mixtures but not for complex formation. For example, a ratio of 4
`
`30
`
`mgof cladribine to 500 mg of cyclodextrin contains too much cyclodextrin, so
`
`5
`
`

`

`WO 2004/087101
`
`PCT/US2004/009387
`
`wil
`
`that the drug would notreadily leave the complex and achieveits therapeutic
`
`function. On the other hand, 15 mg of cladribine and only 100 mgof
`cyclodextrin would not be enough to complex that amountof cladribine.
`
`The Schultz et a/. patent does suggest improving the stability of
`cladribine in oral dosage forms by combining/complexing it with cyclodextrin,
`
`but does not suggest improving the drug’s oral bioavailability by such means;
`
`in fact, the patent does not describe or suggest a method for enhancing or
`
`maximizing the bioavailability of cladribine from a solid oral dosage form of
`
`cladribine and cyclodextrin, or a composition specially designed to do so.
`
`10
`
`Many workers have studied the solubility of specific drugs in water
`
`containing various concentrations of selected cyclodextrins in order to
`
`demonstrate that increasing concentrations of cyclodextrins increase the
`
`solubility of the drugs at selected temperatures and pH levels, as for
`
`example reported in the Schultz et a/. patent. Phase solubility studies have
`
`15
`
`also been performed by various workers in orderto elucidate the nature of
`
`the complex formation, for example, whether the cyclodextrin and drug form
`
`a 1:1 complex or a 1:2 complex; see, for example, Harada et a/. U.S. Patent
`
`No. 4,497,803, relating to inclusion complexes of lankacidin-group antibiotics
`
`with cyclodextrin, and Shinoda et al. U.S. Patent No. 4,478,995, relating to a
`
`20
`
`complex of an acid addition salt of (2'-benzyloxycarbonyl)pheny! trans-4-
`
`guanidinomethylcyclohexanecarboxylate with a cyclodextrin.
`
`While Schultz ef al. teach that a cladribine-cyclodextrin complex
`
`improves the water solubility and acid stability of cladribine, the art does not
`
`suggest how to maximize or enhance the benefits of the complexation in
`
`25
`
`terms of bioavailability and interpatient variation when the complexis to be
`
`administered in a solid oral dosage form.
`
`6
`
`

`

`WO 2004/087101
`
`PCT/US2004/009387
`
`-5-
`
`SUMMARYOF THE INVENTION
`
`li has now been found that amorphous cyclodextrins can be combined
`
`with cladribine to form @ particularly advantageous product which cen be
`
`incorporated into a solid oral dosage form. This product is a complex
`
`cladribine-cyclodextrin complex, and the solid oral dosage form containingit
`
`improvesoral bioavailability and/or achieves lowerinterpatient and/or
`intrapatient variation of the drug.
`
`The present invention provides a complex cladribine-cyclodextrin
`
`complex whichis an intimate amorphous admixture of (a) an amorphous
`
`10
`
`inclusion complex of cladribine with an amorphouscyclodextrin and (b)
`
`amorphousfree cladribine associated with amorphous cyclodextrin as a non-
`
`inclusion complex, and a pharmaceutical composition comprising said
`
`complex, formulated into a solid oral dosage form. Thus, the cyclodextrin
`
`itself is amorphous,the inclusion complex with cladribine is amorphous (and
`
`15
`
`is preferably saturated with cladribine) and the free cladribine which forms
`
`the non-inclusion complex is amorphous.
`
`The invention also provides a method for increasing or enhancing the
`
`oral bioavailability of cladribine comprising orally administering to a subjectin
`
`need thereof, a pharmaceutical composition comprising a complex
`
`20
`
`cladribine-cyclodextrin complex which is an intimate amorphous admixture of
`
`(a) an amorphousinclusion complexof cladribine with an amorphous
`
`cyclodextrin and (b) amorphousfree cladribine associated with amorphous
`
`cyclodextrin as a non-inclusion complex, formulated into a solid oral dosage
`
`form which maximizes the amount of cladribine in the inclusion and non-
`
`25
`
`inclusion complexes.
`
`The invention further provides for treatment of conditions responsive
`
`to administration of cladribine in mammals by administering thereto the
`
`composition of the invention. Use of cladribine in the preparation of the
`
`pharmaceutical compositions of the invention for administration to treat
`
`7
`
`

`

`WO 2004/087101
`
`PCT/US2004/009387
`
`-6-
`
`cladribine-responsive conditions and for enhancing the oral bioavailability of
`
`cladribine is also provided.
`
`Still further, the invention provides 2 process for the preparation of a
`
`complex cladribine-cyclodextrin complex which comprises the stepsof:
`
`(i) combining cladribine and an amorphouscyclodextrin in water at a
`
`temperature of from about 40 to about 80°C and maintaining said
`
`temperature for a period of from about 6 to about 24 hours;
`
`(ii) cooling the resultant aqueous solution to room temperature; and
`
`(iii)
`
`lyophilizing the cooled solution to afford an amorphous product.
`
`10
`
`In yet a further aspect the invention provides a pharmaceutical
`
`composition obtainable by a process comprising the stepsof:
`
`(i) combining cladribine and an amorphouscyclodextrin in water at a
`
`temperature of from about 40 to about 80°C and maintaining said
`
`temperature for a period of from about 6 to about 24 hours;
`
`15
`
`(iil) cooling the resultant aqueoussolution to room temperature;
`
`(iii)
`
`lyophilizing the cooled solution to afford an amorphous product;
`
`and
`
`(iv) formulating the amorphousproductinto a solid oral dosage form.
`
`20
`
`BRIEF DESCRIPTION OF THE DRAWING
`
`A more complete appreciation of the invention and its many attendant
`
`advantageswill be readily understood by reference to the following detailed
`
`description and the accompanying drawing, wherein the sole Figure is a
`
`graphical representation of the results of a phase solubility study where
`
`25
`
`various molar concentrations of hydroxypropyl-8-cyclodextrin (HPBCD) are
`
`plotted against various cladribine molar concentrations, with (@) representing
`
`8
`
`

`

`WO 2004/087101
`
`PCT/US2004/009387
`
`pe
`
`the data points obtained for complexation under conditions specified in
`EXAMPLE 2 below.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Throughoutthe instant specification and claims, the following
`
`definitions and general statements are applicable.
`
`The patents, published applications, and scientific literature referred
`
`to herein establish the knowledge of those with skill in the art and are hereby
`
`incorporated by reference in their entirety to the same extent as if each was
`
`10
`
`specifically and individually indicated to be incorporated by reference. Any
`conflict between any reference cited herein and the specific teachings of this
`specification shall be resolved in favor of the latter. Likewise, any conflict
`
`between an art-understood definition of a word or phrase and a definition of
`
`the word or phrase asspecifically taught in this specification shall be
`
`15
`
`resolvedin favorofthe latter.
`
`The term “inclusion complex” as used herein refers to a complex of
`
`cladribine with the selected cyclodextrin wherein the hydrophobic portion of
`
`the cladribine molecule (the nitrogen-containing ring system)is inserted into
`
`the hydrophobic cavity of the cyclodextrin molecule. This is often referred to
`
`20
`
`simply as a cyclodextrin complex of the drug.
`
`The term'“non-inclusion complex” refers to a complex whichis not an
`
`inclusion complex; rather than the hydrophobic portion of cladribine being
`
`inserted in the cyclodextrin cavity, the non-inclusion complex is formed
`
`primarily by hydrogen-bonding of the hydroxyls and amino group on “free”
`
`25
`
`cladribine, (i.e. cladribine not in the inclusion complex) to the hydroxyls on
`
`the exterior of the cyclodextrin torus (e.g. in the case of hydroxypropy!-B-
`
`cyclodextrin, hydroxypropyl and hydroxyl groups on the glucose rings). This
`
`is a more loosely-held association than an inclusion complex.
`
`9
`
`

`

`WO 2004/087101
`
`PCT/US2004/009387
`
`-8-
`
`As used herein, whetherin a transitional phrase or in the body of a
`
`claim, the terms “comprise(s)” and “comprising” are to be interpreted as
`
`having an open-ended meaning. Thatis, the terms are to be interpreted
`
`synonymously with the phrases “having at least” or “including at least”.
`
`When usedin the context of a process, the term “comprising” meansthat the
`
`processincludesat least the recited steps, but may include additional steps.
`
`Whenusedin the context of a composition, the term “comprising” means
`
`that the composition includes at least the recited features or components,
`
`but may also include additional features or components.
`
`10
`
`The terms “consists essentially of’ or “consisting essentially of’ have a
`
`partially closed meaning, that is, they do not permit inclusion of steps or
`
`features or components which would substantially change the essential
`
`characteristics of a process or composition; for example, steps or features or
`
`components which would significantly interfere with the desired properties of
`
`15
`
`the compositions described herein, /.e., the process or compositionis limited
`
`20
`
`25
`
`to the specified steps or materials and those which do not materially affect
`
`the basic and novel characteristics of the invention. The basic and novel
`
`features herein are the provision of a complex cladribine-cyclodextrin
`
`complex whichis an intimate.amorphous admixture of (a) an amorphous
`
`inclusion complex of cladribine with an amorphouscyclodextrin and (b)
`amorphousfree cladribine associated with amorphous cyclodextrin as a non-
`inclusion complex, formulated into a solid oral dosage form, so as to provide
`
`improved bioavailability and/or lower interpatient and/orintrapatient variation
`following administration. Essential to the invention is the combination of the
`amorphous nature of the starting cyclodextrin, and the level of water
`
`solubility exhibited by cladribine (about 5 mg/ml at room temperature), and
`
`consequentlyits capability for hydrogen bonding, which can be taken
`
`advantage of underparticular conditions described hereinafter, and which
`
`afford a special amorphous mixture uniquely well-suited for optimizing the
`
`30
`
`oral bioavailability of cladribine.
`
`10
`
`10
`
`

`

`WO 2004/087101
`
`PCT/US2004/009387
`
`-9-
`
`The terms “consists of’ and “consists” are closed terminology and
`
`allowonly for the inclusion of the recited steps or features or componenis.
`mit
`
`As used herein, the singular forms “a,”
`
`“an” and “the” specifically also
`
`encompassthe plural forms of the terms to which they refer, unless the
`
`content clearly dictates otherwise.
`
`The term “about” is used herein to means approximately, in the region
`
`of, roughly, or around. Whenthe term “about” is used in conjunction with a
`
`numerical range, it modifies that range by extending the boundaries above
`
`and below the numerical values set forth.
`
`In general, the term “about” or
`
`10
`
`“approximately” is used herein to modify a numerical value above and below
`
`the stated value by a variance of 20%.
`
`The term “amorphous”is used herein to refer to a noncrystalline solid.
`The cyclodextrins encompassed herein themselves are amorphous because
`they are each composedof a multitude of individual isomers, and their
`
`15
`
`complexes with cladribine are also amorphous. Further, conditions for
`
`complexation can be selected (elevated temperature and prolonged
`
`complexation times, as described hereinafter) so that a supersaturated
`
`cladribine solution will be formed. When cooled, because of the amorphous
`
`nature of the complex and the cyclodextrin, some excessfree cladribine
`
`20
`
`does not precipitate but rather is trapped in amorphousform in intimate
`
`admixture with the (preferably saturated) amorphouscladribine-cyclodextrin
`
`inclusion complex. This excess cladribine forms a loosely-held association,
`
`or non-inclusion complex, with the cyclodextrin through hydrogen bonding.
`
`This, then, further increases the amountof cladribine in the product;this
`
`25
`
`additional cladribine, becauseit is amorphous and also becauseit is in
`
`intimate admixture with the amorphousinclusion complex, is expected to be
`
`somewhatprotected from degradation by stomachacid (although it may not
`
`be as protected as the cladribine whichis in the form of the inclusion
`
`complex).
`
`11
`
`11
`
`

`

`WO 2004/087101
`
`PCT/US2004/009387
`
`-10-
`
`The term “saturated” when used in conjunction with a complex of
`
`cladribine in amorphous cyclodextrin means that the cornplexis saturated
`
`with cladribine, that is, the complex contains the maximum amountof
`
`cladribine which can be complexed (by meansof both inclusion and non-
`
`inclusion complexes) with a given amount of cyclodextrin underthe
`
`conditions of complexation used. A phase solubility study can be used to
`
`provide this information, as described in more detail hereinafter. (Conditions
`
`for the complexation are also described in more detail below.) Alternatively,
`
`a saturated complex may bearrived at empirically by simply adding
`
`10
`
`cladribine to an aqueoussolution of the selected cyclodextrin until no more
`
`cladribine goesinto solution; ultimately, excess cladribine, if any, is removed
`
`(byfiltration or centrifugation) and the solution lyophilized to provide the dry
`
`saturated complex.
`
`The expression “substantially’, as in “substantially free” means within
`
`15
`
`20%of the exact calculated amount, preferably within 10%, most preferably
`
`within 5%.
`
`The term “interpatient variability” refers to variation among patients to
`
`which a drug is administered. The term “intrapatient variability” refers to
`
`variation experienced by a single patient when dosed atdifferent times.
`
`20
`
`As used herein, the recitation of a numerical rangefor a variableis
`
`intended to convey that the invention may be practiced with the variable
`
`equalto any ofthe values within that range. Thus, for a variable whichis
`
`inherently discrete, the variable can be equal to any integer value of the
`
`numerical range, including the end-points of the range. Similarly, for a
`
`25
`
`variable which is inherently continuous, the variable can be equal to any real
`
`value of the numerical range, including the end-points of the range. As an
`
`example, a variable which is described as having values between 0 and 2,
`
`can be 0, 1 or 2 for variables which are inherently discrete, and can be 0.0,
`
`12
`
`12
`
`

`

`WO 2004/087101
`
`PCT/US2004/009387
`
`-11-
`
`0.1, 0.01, 0.001, or any other real value for variables which are inherently
`
`continuous.
`
`In the specification and claims, the singular forms include plural
`
`referents unless the context clearly dictates otherwise. As used herein,
`
`unless specifically indicated otherwise, the word “or”is usedin the “inclusive”
`
`sense of “and/or” and not the “exclusive” sense of“either/or.”
`
`Technical and scientific terms used herein have the meaning
`
`commonly understood by oneofskill in the art to which the present invention
`
`pertains, unless otherwise defined. Reference is made herein to various
`
`10
`
`methodologies and materials known to those ofskill in the art. Standard
`
`reference workssetting forth the general principles of pharmacology include
`Goodmanand Gilman’s The Pharmacological Basis of Therapeutics, 10"
`Ed., McGraw Hill Companies Inc., New York (2001).
`
`Reference is made hereinafter in detail to specific embodiments of the
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`invention. While the invention will be described in conjunction with these
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`specific embodiments, it will be understood thatit is not intendedtolimit the
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`invention to such specific embodiments. On the contrary,it is intended to
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`coveralternatives, modifications, and equivalents as may beincluded within
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`the spirit and scope of the invention as defined by the appendedclaims.
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`In
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`the following description, numerous specific details are set forth in order to
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`provided a thorough understanding of the present invention. The present
`invention may be practiced without someorall of these specific details. In
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`other instances, well-known process operations have not been described in
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`detail, in order not to unnecessarily obscure the present invention.
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`There is provided by the present invention compositions, as well as
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`methods of making and of using pharmaceutical compositions, useful to
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`achieve desirable pharmacokinetic properties. Such compositions stem from
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`the discovery that solutions of cyclodextrin and cladribine in which cladribine
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`is in a high thermodynamic state, when presented to the gastric mucosa
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`through which they are absorbed are associated with improved cladribine
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`absorption, as reflected by higher bioavailability and/or lowerinterpatient
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`variation.
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`It is postulated, without wishing to solimit the invention, that upon
`dissolution (e.g., by contact with a fluid, such as a bodily fluid), dry
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`compositions according to the invention form a locally saturated cladribine
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`solution in which cladribineis in the state of highest thermodynamic activity
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`(HTA), thus favoring absorption. Cladribine hasa fairly low, although not
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`insignificant, intrinsic aqueoussolubility; it is in fact somewhat water soluble.
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`The free cladribine formed from dissociation of the inclusion and non-
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`inclusion complexes in a saturated aqueoussolution seeks a more stable
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`activity level by being absorbed through the gastric mucosa.
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`In view of the foregoing, it is apparent that to produce optimal
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`pharmaceutical compositions, in a solid oral dosage form, these dosage
`forms should be formulated to release a localized saturated cladribine
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`solution, upon contact of the solid dosage forms with bodyfluid at the
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`mucosa, in which cladribineis in its HTA state. To provide suchalocalized
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`saturated solution in vivo, it is importantto first identify the optimal ratio of
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`cladribine to amorphous cyclodextrin, which ratio is referred to herein as the
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`HTAratio, to be used in the solid dosage form.
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`The HTAratio is empirically determined andis identified as the ratio
`of cladribine to amorphous cyclodextrin which corresponds to the maximum
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`amountof cladribine that can be complexed with a given amountof the
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`cyclodextrin. The HTA ratio may be determined using an empirical method
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`such as a phasesolubility study to determine the saturation concentration of
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`cladribine that can be solubilized with different concentrations of amorphous
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`cyclodextrin solutions. Hence, the methodidentifies the concentrations at
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`which a saturated cladribine-cyclodextrin complexis formed.
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`It is noted that
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`the molar ratio represented by a point on the phasesolubility graph shows
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`how many moles of amorphous cyclodextrin are the minimum needed to
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`maintain the drug in the complex, under given conditions; this may then be
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`converted to a weight ratio. For example, if a phase solubility diagram
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`showsthat 9 moles of a given cyclodextrin are needed to maintain the
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`cladribine in a saturated complex, then multiplying the numberof moles of
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`cladribine by its molecular weight and multiplying the number of moles of the
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`selected cyclodextrin by its molecular weight, one can arrive at the ratio of
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`the products as an appropriate optimized weight ratio. A phase solubility
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`study also provides information about the nature of the cladribine-
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`cyclodextrin inclusion complex formed, for example whetherthe inclusion
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`complex is a 1:1 complex (1 molecule of drug complexed with 1 molecule of
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`cyclodextrin) or a 1:2 complex (1 molecule of drug complexed with 2
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`molecules of cyclodextrin).
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`In accordance with the present invention, one can start using either
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`the selected amorphouscyclodextrin, such as hydroxypropyl-8-cyclodextrin
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`(HPBCD)or hydroxypropyl-y-cyclodextrin, or cladribine as the fixed variable
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`to which an excessof the other is added to identify various solubility data
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`points (indicating saturated cladribine-cyclodextrin complexes) and draw the
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`resultant line. Typically, cladribine is added to an aqueous solution having a
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`known concentration of amorphous cyclextrin under conditions empirically
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`found to promote complex formation. Generally, the complexation is
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`conducted with heating, for example at about 45 to about 60°C fora
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`significant period of time, e.g., at least 6-9 hours; it is believed that even
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`better results can be obtained by heating at up to about 80°C for up to 24
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`hours. Excessprecipitated cladribine is then removedand thecladribine
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`concentration is subsequently measured. This concentration represents the
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`amountof cladribine solubilized for a given amorphous cyclodextrin
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`concentration. This process is repeated for a different known concentration
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`of cyclodextrin until several data points are obtained. Each data point
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`represents the concentration of the cladribine dissolved in a known
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`concentration of the selected amorphouscyclodextrin. The data points are
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`then plotted to showthe conceniration of cladribine against the various
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`cyclodextrin concentrations used. The graph is a phasesolubility diagram
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`which can be used to determine the amountof cladribine for any specific
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`concentration of cyclodextrin used to form the solution under a given set of
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`It will be appreciated that the aqueous solubility of
`complexation conditions.
`cladribine is about 5 mg/ml at room temperature and would be higherat
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`elevated temperature. Consequently, the data points correspond to the
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`amountof cladribine dissolved in aqueous HPBCD orother amorphous
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`cyclodextrin under the selected conditions; whenlater lyophilized, the
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`solution yields a complex cladribine-cyclodextrin complex whichis an
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`intimate amorphous admixture of (a) an amorphous inclusion complex of
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`cladribine with an amorphous cyclodextrin and (b) amorphousfree cladribine
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`associated with amorphouscyclodextrin as a non-inclusion complex.
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`If
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`equilibrium conditions are reached during the complexation, the amorphous
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`cladribine-cyclodextrin complexwill be saturated with cladribine.
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`One ofskill in the art will appreciate that concentrations at which
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`saturated complexesof cladribine with amorphous cyclodextrins are formed
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`(and thus HTA ratios as well) may be identified by a variety of alternative
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`methodologies. Accordingly, any method knownin thefield suitable to
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`identify these concentrations is within the scope of the invention.
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`lt has been discovered that desirable pharmacological properties
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`(improved bioavailability and/or coefficient of variation as compared to
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`traditional approaches) are associated with mixtures of inclusion complexes
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`25
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`and non-inclusion complexesof cladribine and cyclodextrin.
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`Usingintrinsically amorphous cyclodextrins, for example
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`hydroxypropyl-B-cyclodextrin, hydroxypropyl-y-cyclodextrin, randomly
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`methylated cyclodextrins, and the like, with cladribine, which is a somewhat
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`water soluble compound (capable of H-bonding through its free hydroxyl and
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`amino groups), the cladribine provides increased solubility in solutions of
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`these cyclodextrins. Not only is there increased water solubility but also H-
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`bonded association of the cladribine with the cyclodextrin, separately from
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`the actual inclusion complexed material.
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`Oneofskill in the art will appreciate that the phase solubility diagram
`
`for each given starting concentration ratio represents the starting point of
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`one's investigation on the basis of which variables (reactants'
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`concentrations, temperature and time) may be altered to promote inclusion
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`complex and non-inclusion complex associations favoring a higher or lower
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`proportion of either type of association in the final product. Departure from
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`the ratio of cladribine to cyclodextrin, the temperature and/or the dilution
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`empirically found to promote equilibrium towards complex formation is then
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`analyzed to promote the formation of mixtures of inclusion complexes and
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`non-inclusion complexes of cladribine and cyclodextrin in various proportions
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`15
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`according to the invention.
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`Thus, for example, by starting with more diluted cyclodextrin (i.e.,
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`larger water volumesthan that used for solubility plot analysis) logically will
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`accommodate morecladribine in solution sequestering more of the same
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`from complex formation. Upon evaporation, some of the solubilized
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`20
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`cladribine will tend to associate with cyclodextrin in a non-inclusion complex
`
`fashion. By altering the initial dilution, one may shift equilibrium towards
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`inclusion complex or non-inclusion complex formation. Similarly, by
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`increasing complexation temperature, the water solubility of cladribine may
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`be increased while decreasing the stability of inclusion complexes, thus
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`25
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`promoting non-inclusion complexes. Thus, by altering complexation
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`temperature, one may shift equilibrium towards inclusion complex or non-
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`inclusion complex formation. Finally, complexation time may bealter