(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
`
`(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
`
`(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)
`
`US
`US
`US
`
`(71) Applicant (for all designated States except US): IVAX
`CORPORATION [US/US]; 4400 Biscayne Boulevard,
`Miami, Florida 33137 (US).
`
`(84)
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): BODOR,Nicholas,
`S. [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).
`
`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, KZ, 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.
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`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, CE, CG, CI, CM, GA, GN, GQ, GW,
`ML, MR,NE,SN,TD, TG).
`
`[Continued on next page]
`
`(54) Title: ORAL FORMULATIONS OF CLADRIBINE
`
`0.080 5
`
`
`
`
`
`Cladribineconc.(M)
`
`0.010 -
`
`
`
`
`0.000
`
`
`T
`T
`T
`T
`T
`1
`
`0.000
`
`0.050
`
`0.100
`
`0.150
`
`0.200
`
`0.250
`
`0.300
`
`CD conc.(M)
`
`(57) Abstract: ABSTRACT OF THE DISCLOSUREProvided are compositions of cladribine and cyclodextrin which are especially
`suited for the oral administration of cladribine.
`
`Petitioner TWi Pharms., Inc.
`EX1007, Page 1 of 56
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`WO2004/087101A2IIMINIMNMIINTANIITNTITAAAATANATAM
`
`Petitioner TWi Pharms., Inc.
`EX1007, Page 1 of 56
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`

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`WO 2004/087101 A2
`
`—_[IMINIMNITNIINTATMIITA TIMI TTAA
`
`Published:
`— without international search report and to be republished
`upon receipt of that 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.
`
`Petitioner TWi Pharms., Inc.
`EX1007, Page 2 of 56
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`Petitioner TWi Pharms., Inc.
`EX1007, Page 2 of 56
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`WO 2004/087101
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`PCT/US2004/009387
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`-1-
`
`ORAL FORMULATIONS OF CLADRIBINE
`
`FIELD OF THE INVENTION
`
`5
`
`The invention relates to a composition comprising a complex
`cladribine-cyclodextrin complex formulated into a solid oral dosage form and
`to a method for enhancing the oral bioavailability of cladribine.
`
`BACKGROUND OF THE INVENTION
`
`Cladribine, which is an acid-labile drug, has the chemical structure as
`
`10
`
`set forth below:
`
`NHo2
`
`i NCACc
`
`—N
`
`N~
`
`HOCH2
`
`O
`
`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 usein the treatment of
`
`lymphoproliferative disorders.
`
`It has been used to treat experimental
`
`leukemias such as L1210 andclinically for hairy cell leukemia and chronic
`
`lymphocytic leukemia as well as Waldenstrom’s macroglobulinaemia.
`
`It has
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`EX1007, Page 3 of 56
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`EX1007, Page 3 of 56
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`-2-
`
`also been used as an immunosuppressive agent and as a modality for the
`treaiment of a 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,
`$2(2): 120-131, 1997).
`It has also been investigated, either experimentally
`orclinically in, for example, lymphomas, Langerhan’scell histiocytosis, lupus
`erythematosus, chronic plaque psoriasis, Sezary syndrome, Bing-Neel
`syndrome, recurrent glioma, and solid tumors.
`
`Oral delivery of drugsis often preferred to parenteraldelivery for a
`variety of reasons, foremost patient compliance, or for cost or therapeutic
`considerations. Patient compliance is enhanced insofar as oral dosage
`forms alleviate repeated health care providervisits, or the discomfort of
`injections or prolonged infusion 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 may be 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 a/., J. Clin. Oncol., 10(10): 1514-
`1518, 1992), and suboptimal interpatient variation (see, e.g., J. Liliemark,
`Clin. Pharmacokinet, 32 (2): 120-131, 1997). See also, A. Tarasuik, etal.
`reporting poor absorption and pH dependentlability (Arch. Immunol. et
`Therapiae Exper., 42: 13-15, 1994).
`
`Cyclodextrins are cyclic oligosaccharides composedofcyclic a-(i1—4)
`linked D-glucopyranose units. Cyclodextrins with six to eight units have
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`EX1007, Page 4 of 56
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`EX1007, Page 4 of 56
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`-3-
`
`been named a-, B- and y-cyclodextrin, respectively. The numberofunits |
`determines the size of the cone-shaped cavity which characterizes
`cyclodextrins and into which drugs may be included to form stable
`complexes. A numberofderivatives of a-, B- and y-cyclodextrin are known
`in which one or more hydroxyl groupsis/are replaced with ether groups or
`otherradicals. These compounds are thus known complexing agents and
`have beenpreviously used in the pharmaceuticalfield to form inclusion
`complexes with water-insoluble drugs and to thus solubilize them in aqueous
`media.
`
`Recently, Schultz ef a/., in U.S. Patent No. 6,194,395 B1, have
`described complexing and solubilizing cladribine with cyclodextrin. The
`Schultz et al. 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
`only significantly more soluble in aqueous media when formulated with
`cyclodextrin, but also is more stable against acid-catalyzed hydrolysis when
`combinedwith 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.
`Schultz eft a/. do not appear to have described any actual work in connection
`with solid oral dosage forms.
`In fact, they describe only one method of
`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 ranges of
`1 mg to 15 mgofcladribine and 100 mg to 500 mg ofcyclodextrin listed in
`the patent suggest nocriticality to the particular amount of cyclodextrin to be
`present with a given amountof cladribine in a solid oral dosage form.
`Indeed, these dosage ranges include many combinations which may be
`suitable as mixtures but not for cornplex formation. For example, a ratio of 1
`mg of cladribine to 500 mg of cyclodextrin contains too much cyclodextrin, so
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`EX1007, Page 5 of 56
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`-4-
`
`that the drug would not readily leave the complex and achieveits therapeutic
`function. On the other hand, 15 mg of cladribine and only 100 mg of
`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/complexingit 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 methodfor 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.
`
`Manyworkers havestudied 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 pHlevels,as for
`example reported in the Schultz ef a/. patent. Phase solubility studies have
`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 Shinodaetal. U.S. Patent No. 4,478,995, relating to a
`complex of an acid addition salt of (2'-benzyloxycarbonyl)pheny!trans-4-
`guanidinomethylcyclohexanecarboxylate with a cyclodextrin.
`
`While Schultz eta/. 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
`termsof bioavailability and interpatient variation when the complexis to be
`administered in a solid oral dosage form.
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`EX1007, Page 6 of 56
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`EX1007, Page 6 of 56
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`PCT/US2004/009387
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`-5-
`
`SUMMARYOF THE INVENTION
`
`lt has now been found that amorphous cyclodextrins can be combined
`with cladribine to form a particularly advantageous product which can 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 lower interpatient and/or
`intrapatient variation of the drug.
`
`The presentinvention provides a complex cladribine-cyclodextrin
`complex which is an intimate amorphous admixture of (a) an amorphous
`inclusion complexof cladribine with an amorphous cyclodextrin 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
`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
`cladribine-cyclodextrin complex whichis 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 amountof cladribine in the inclusion and non-
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`
`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
`
`Petitioner TWi Pharms., Inc.
`EX1007, Page 7 of 56
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`Petitioner TWi Pharms., Inc.
`EX1007, Page 7 of 56
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`-6-
`
`cladribine-responsive conditions and for enhancing the oral bioavailability of
`cladribine is also provided.
`
`Still further, the invention provides a process for the preparation of a
`complex cladribine-cyclodextrin complex which comprises the steps of:
`
`(i) combining cladribine and an amorphous cyclodextrin in waterat 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 aqueoussolution to room temperature; and
`
`(iii)
`
`lyophilizing the cooled solution to afford an amorphousproduct.
`
`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
`
`(ii) cooling the resultant aqueous solution to room temperature;
`
`(iii)
`
`lyophilizing the cooled solution to afford an amorphous product:
`
`and
`
`(iv) formulating the amorphous productinto a solid oral dosage form.
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`20
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`25
`
`BRIEF DESCRIPTION OF THE DRAWING
`
`A more complete appreciation of the invention and its many attendant
`advantageswill be readily understood by referenceto 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
`various molar concentrations of hydroxypropyl-8-cyclodextrin (HP8CD)are
`plotted against various cladribine molar concentrations,with (@) representing
`
`Petitioner TWi Pharms., Inc.
`EX1007, Page 8 of 56
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`EX1007, Page 8 of 56
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`-7-
`
`the data points obtained for complexation under conditions specified in
`EXAMPLE 2 beiow.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Throughout the instant specification and claims, the following
`definitions and general statements are applicable.
`
`The patents, published applications, and scientific literature referred
`to herein establish the knowledgeof those with skill in the art and are hereby
`incorporated by referencein their entirety to the same extent as if each was
`specifically and individually indicated to be incorporated by reference. Any
`conflict between any reference cited herein and the specific teachingsof this
`specification shall be resolved in favorofthe latter. Likewise, any conflict
`between an art-understood definition of a word or phrase and a definition of
`the word or phrase as specifically taught in this specification shall be
`resolved in favorofthe latter.
`
`The term “inclusion complex’ as used herein refers to a complexof
`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
`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”
`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 hydroxypropyl-B-
`cyclodextrin, hydroxypropyl and hydroxyl groups on the glucose rings). This
`is a more loosely-held association than an inclusion complex.
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`EX1007, Page 9 of 56
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`Petitioner TWi Pharms., Inc.
`EX1007, Page 9 of 56
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`PCT/US2004/009387
`
`-8-
`
`As used herein, whetherin a transitional phrase orin 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” meansthatthe
`process includesatleast the recited steps, but may include additional steps.
`When usedin the context of a composition, the term “comprising” means
`that the composition includes at least the recited features or components,
`but mayalso include additional features or components.
`
`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
`the compositions described herein, i.e., the process or compositionis limited
`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 which is an intimate. amorphous admixture of (a) an amorphous
`inclusion complex of cladribine with an amorphouscyclodextrin and (b)
`amorphousfree cladribine associated with amorphouscyclodextrin as a non-
`inclusion complex, formulated into a solid oral dosage form, so as to provide
`improved bioavailability and/or lowerinterpatient and/orintrapatient variation
`following administration. Essential to the invention is the combination of the
`amorphousnature of the starting cyclodextrin, and the level of water
`solubility exhibited by cladribine (about 5 mg/ml at room temperature), and
`consequently its 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
`oral bioavailability of cladribine.
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`EX1007, Page 10 of 56
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`EX1007, Page 10 of 56
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`-9-
`
`The terms “consists of’ and “consists” are closed terminology and
`allow only for the inclusion of the recited steps or features or components.
`ik
`tt
`“an” and “the” specifically also
`As used herein, the singular forms “a,”
`encompassthe plural formsof the terms to whichthey 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
`“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 hereinto refer to a noncrystalline solid.
`The cyclodextrins encompassed herein themselves are amorphous because
`they are each composedof a multitudeof individual isomers, andtheir
`complexeswith cladribine are also amorphous. Further, conditionsfor
`complexation can be selected (elevated temperature and prolonged
`complexation times, as described hereinafter) so that a supersaturated
`cladribine solution will be formed. When cooled, becauseof the amorphous
`nature of the complex and the cyclodextrin, some excessfree cladribine
`does notprecipitate but ratheris trapped in amorphousform in intimate
`admixture with the (preferably saturated) amorphous cladribine-cyclodextrin
`inclusion complex. This excesscladribine 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
`additional cladribine, becauseit is amorphous and also becauseit is in
`intimate admixture with the amorphousinclusion complex,is expected to be
`somewhat protected from degradation by stomach acid (although it may not
`be as protected as the cladribine which is in the form of the inclusion
`complex).
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`EX1007, Page 11 of 56
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`EX1007, Page 11 of 56
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`-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 under the
`conditions of complexation used. A phase solubility study can be used to
`providethis information, as described in more detail hereinafter.
`(Conditions
`for the complexation are also described in more detail below.) Alternatively,
`a saturated complex may be arrived at empirically by simply adding
`cladribine to an aqueoussolution of the selected cyclodextrin until no more
`cladribine goesinto solution; ultimately, excesscladribine,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
`20% of the exact calculated amount, preferably within 10%, most preferably
`within 5%.
`
`The term “interpatient variability” refers to variation amongpatients to
`which a drug is administered. The term “intrapatient variability” refers to
`variation experienced by a single patient when dosedatdifferent times.
`
`Asused herein, the recitation of a numerical range for a variable is
`intended to convey that the invention may bepracticed with the variable
`equalto any of the values within that range. Thus, for a variable whichis
`inherently discrete, the variable can be equal to any integer value of the
`numericalrange, including the end-points of the range. Similarly, fora
`variable whichis inherently continuous, the variable can be equalto 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,
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`EX1007, Page 12 of 56
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`-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 used in the “inclusive”
`sense of “and/or” and not the “exclusive” senseof“either/or.”
`
`Technical and scientific terms used herein have the meaning
`commonly understood by oneofskill in the art to which the presentinvention
`pertains, unless otherwise defined. Reference is made herein to various
`methodologies and materials knownto thoseofskill in the art. Standard
`reference workssetting forth the generalprinciples of pharmacology include
`Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10"
`Ed., McGraw Hill CompaniesInc., New York (2001).
`
`Reference is made hereinafterin detail to specific embodiments of the
`invention. While the invention will be described in conjunction with these
`specific embodiments,it will be understoodthatit is not intended to limit the
`invention to such specific embodiments. On the contrary,it is intended to
`coveralternatives, modifications, and equivalents as may be included within
`the spirit and scope of the invention as defined bythe appendedclaims.
`In
`the following description, numerous specific details are set forth in order to
`provided a thorough understanding of the present invention. The present
`invention may be practiced without someorall of these specific details. In
`otherinstances, well-known process operations have not been described in
`detail, in order not to unnecessarily obscure the presentinvention.
`
`There is provided by the present invention compositions, as well as
`methods of making and of using pharmaceutical compositions, useful to
`achieve desirable pharmacokinetic properties. Such compositions stem from
`the discovery that solutions of cyclodextrin and cladribine in whichcladribine
`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
`absorption, as reflected by higher bioavailability and/or lower interpatient
`variation.
`
`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
`compositions according to the invention form a locally saturated cladribine
`solution in which cladribineis in the state of highest thermodynamic activity
`(HTA), thus favoring absorption. Cladribine hasa fairly low, although not
`insignificant, intrinsic aqueoussolubility; it is in fact somewhat water soluble.
`The free cladribine formed from dissociation of the inclusion and non-
`inclusion complexes in a saturated aqueous solution seeks a more stable
`activity level by being absorbed through the gastric mucosa.
`
`In view ofthe foregoing, it is apparent that to produce optimal
`pharmaceutical compositions, in a solid oral dosage form, these dosage
`forms should be formulated to release a localized saturated cladribine
`solution, upon contact of the solid dosage forms with bodyfluid at the
`mucosa, in which cladribine is in its HTA state. To provide such a localized
`saturatedsolution in vivo,it is importantto first identify the optimalratio of
`cladribine to amorphous cyclodextrin, which ratio is referred to herein as the
`HTAratio, to be used in the solid dosage form.
`
`The HTAratio is empirically determined andis identified as the ratio
`of cladribine to amorphous cyclodextrin which correspondsto the maximum
`amountof cladribine that can be complexed with a given amountof the
`cyclodextrin. The HTA ratio may be determined using an empirical method
`such as a phasesolubility study to determine the saturation concentration of
`cladribine that can be solubilized with different concentrations of amorphous
`cyclodextrin solutions. Hence, the method identifies the concentrations at
`which a saturated cladribine-cyclodextrin complexis formed.
`It is noted that
`the molarratio represented by a point on the phasesolubility graph shows
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`how many moles of amorphous cyclodextrin are the minimum needed to
`maintain the drug in the complex, under given conditions: this may then be
`converted to a weightratio. For example,if a phase solubility diagrarn
`showsthat 9 molesof a given cyclodextrin are needed to maintain the
`cladribine in a saturated complex, then multiplying the numberof moles of
`cladribine by its molecular weight and multiplying the numberof moles of the
`selected cyclodextrin by its molecular weight, one canarrive at the ratio of
`the products as an appropriate optimized weightratio. A phasesolubility
`study also provides information about the nature of the cladribine-
`cyclodextrin inclusion complex formed, for example whetherthe inclusion
`complex is a 1:1 complex (1 molecule of drug complexed with 1 molecule of
`cyclodextrin) or a 1:2 complex (1 molecule of drug complexed with 2
`molecules of cyclodextrin).
`
`In accordance with the present invention, one canstart using either
`the selected amorphouscyclodextrin, such as hydroxypropyl-B-cyclodextrin
`(HPBCD)or hydroxypropyl-y-cyclodextrin, or cladribine as thefixed variable
`to which an excessof the other is added toidentify various solubility data
`points (indicating saturated cladribine-cyclodextrin complexes) and draw the
`resultantline. Typically, cladribine is added to an aqueoussolution having a
`known concentration of amorphouscyclextrin under conditions empirically
`found to promote complex formation. Generally, the complexationis
`conducted with heating, for example at about 45 to about 60°C fora
`significant periodof time, e.g., at least 6-9 hours;it is believed that even
`better results can be obtained by heating at up to about 80°C for up to 24
`hours. Excessprecipitated cladribine is then removed andthe cladribine
`concentration is subsequently measured. This concentration represents the
`amountof cladribine solubilized for a given amorphouscyclodextrin
`concentration. This processis repeated for a different known concentration
`of cyclodextrin until several data points are obtained. Each data point
`represents the concentration of the cladribine dissolved in a known
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`concentration of the selected amorphous cyclodextrin. The data points are
`then plotted to show the conceniration of cladribine against the various
`cyclodextrin concentrations used. The graph is a phase solubility diagram
`which can be used to determine the amountof cladribine for any specific
`concentration of cyclodextrin used to form the solution undera givensetof
`complexation conditions.
`It will be appreciated that the aqueous solupility of
`cladribine is about 5 mg/ml at room temperature and would be higherat
`elevated temperature. Consequently, the data points correspond to the
`amountof cladribine dissolved in aqueous HPBCDorother amorphous
`cyclodextrin under the selected conditions; whenlater lyophilized, the
`solution yields a complex cladribine-cyclodextrin complex which is an
`intimate amorphous admixture of (a) an amorphousinclusion complex of
`cladribine with an amorphouscyclodextrin and (b) amorphousfree cladribine
`associated with amorphouscyclodextrin as a non-inclusion complex.
`If
`equilibrium conditions are reached during the complexation, the amorphous
`cladribine-cyclodextrin complexwill be saturated with cladribine.
`
`Oneof skill in the art will appreciate that concentrations at which
`saturated complexesof cladribine with amorphous cyclodextrins are formed
`(and thus HTAratios as well) may be identified by a variety ofalternative
`methodologies. Accordingly, any method knownin thefield suitable to
`identify these concentrations is within the scope of the invention.
`
`It has been discovered that desirable pharmacological properties
`(improved bioavailability and/or coefficient of variation as compared to
`traditional approaches) are associated with mixtures ofinclusion complexes
`and non-inclusion complexesof cladribine and cyclodextrin.
`Using intrinsically amorphouscyclodextrins, for example
`hydroxypropyl-B-cyclodextrin, hydroxypropyl-y-cyclodextrin, randomly
`methylated cyclodextrins, and the like, with cladribine, which is a somewhat
`water soluble compound(capable of H-bonding throughits free hydroxyl and
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`amino groups), the cladribine provides increased solubility in solutions of
`these cyclodextrins. Not only is there increased water solubility but also H-
`bonded association of the cladribine with the cyclodextrin, separately from
`the actual inclusion complexed material.
`
`Oneofskill in the art will appreciate that the phase solubility diagram
`for each given starting concentration ratio represents the starting point of
`one's investigation on the basis of which variables (reactants’
`concentrations, temperature and time) may be altered to promote inclusion
`complex and non-inclusion complex associations favoring a higheror lower
`proportion ofeither type of association in the final product. Departure from
`the ratio of cladribine to cyclodextrin, the temperature and/orthedilution
`empirically found to promote equilibrium toward