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`APPLICATION THAT MET THE REQUIREMENTS TO BE GRANTED A
`FILING DATE UNDER35 USC111.
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`UNITED STATES DEPARTMENT OF COMMERCE
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`United States Patent and Trademark Office
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`June 03, 2004
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`THIS IS TO CERTIFY THAT ANNEXED HERETO IS A TRUE COPY FROM
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`OFFICE OF THOSE PAPERS OF THE BELOW IDENTIFIED PATENT
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`APPLICATIONNUMBER: 60/541,247
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`FILING DATE: February 04, 2004
`
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`/PRIORITY DOCUMENT
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`COMMISSIONER OF PATENTS AND TRADEMARKS
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`N.
`WILLIAMS
`Certifying Officer
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`Merck 2046
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`TWi v Merck
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`
`Merck 2046
`TWi v Merck
`IPR2023-00049
`
`

`

`
`
`
`RECD 26 JUL 2004
`
`PA 1178182
`
`10ALENOWHOMHOMTHESE;ERESENES,SSHANE,COMM
`
`
`
`UNITED STATES DEPARTMENT OF COMMERCE
`
`United States Patent and Trademark Office
`
`
`
`June 03, 2004
`
`
`THIS IS TO CERTIFY THAT ANNEXED HERETOIS A TRUE COPY FROM
`THE RECORDSOF THE UNITED STATES PATENT AND TRADEMARK
`
`
`OFFICE OF THOSE PAPERS OF THE BELOW IDENTIFIED PATENT
`APPLICATION THAT MET THE REQUIREMENTSTO BE GRANTED A
`
`
`FILING DATE UNDER35 USC 111.
`
`APPLICATIONNUMBER: 60/541,247
`
`ys/o4ou
`
`GE3bR
`
`FILING DATE: February 04, 2004
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`PRIORITY DOCUMENT
`‘SUBMITTED OR TRANSMITTEDIN
`COMPLIANCE WITH
`RULE 17.1(a) OR (b)
`
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`Certifying Officer
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`Sy: Mle
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`COMMISSIONER OF PATENTS AND TRADEMARKS
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`
`
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`

`

`PATENT APPLICATION SERIAL NO.
`
`U.S. DEPARTMENT OF COMMERCE
`PATENT AND TRADEMARK OFFICE
`FEE RECORD SHEET
`
`02/09/2004 FMETEKI 00000018 60541247
`01 FC:1005
`160.00 OP
`
`PTO-1556
`(5/87)
`
`"U.S. Govemmont Printing Office: 2001 — 481-697/59173
`
`Copy provided by USPTO from the PAGR Image Natahaaa nn nainalonna
`
`

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`‘
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`"
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`>= a
`oS &
`PTOISB/16 (10-01)
`=>
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`oS — ed forusethrough 10/31/2002. OMB 0651-00370.>"
`“== ©& customer Number 21839
`Patentand TrademarkOffice:U.S.DEPARTMENTOFCOMMERCEY)OY
`=3
`°5
`S
`o®
`
`PROVISIONAL APPLICATION FOR PATENT COVER SHEET
`This is a request for filing a PROVISIONAL APPLICATION FOR PATENTunder37 C.F.R. § 1.53(c).
`Docket
`Type a plus sign
`
`
`INVENTOR(s)/APPLICANT(s)
`FIRST NAME
`MIDDLEINITIAL
`
`Number 033935-005|(+) inside this box| +
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`LAST NAME
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`BODOR
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`Nicholas
`
`Ss.
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`RESIDENCE(CITY AND EITHER STATE OR
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`10101 Colllins Avenue, #4
`Bal Harbour, Florida 33154
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`CO) Additionalinventors are being named onthe ___separately numbered sheets attached hereto.
`TITLE OF THE INVENTION(500 characters max)
`.
`
`ORAL FORMULATIONS OF CLADRIBINE
`
`
`CORRESPONDENCE ADDRESS
`
`Burns, Doane, Swecker & Mathis, L.L.P.
`
`
`
`I
`cd
`
`
`
`=
`United States of
`
`
`
`
`
`
`ENCLOSEDAPPLICATION PARTS (checkall that apply)
`4] Specification NumberofPages 28
`. El Other(specify) Claims 1-45 (7pgs)), Abstract (1
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`[] Drawing(s)—Nurhberof Sheets 1 ° PQ) . -
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`‘C1 Application Data Sheet. See 37 CFR 1.76
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`METHOD OF PAYMENTOFFILING FEES FOR THIS PROVISIONAL APPLICATION FOR PATENT (check one)
`(2 Applicant claims smallentity status. See 37 C.F.R. § 1.27.
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`filing fees.
`[] The Directoris hereby authorized to charge anydeficiency in
`filing fees or credit any overpaymentto Deposit Account No.
`02-4800. This paperis submitted in duplicate.
`‘
`4
`The invention was made byan agency of the United States Governmentor under a contract with an agency of the United States Government,
`Ex] No.
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`C1 Yes,the nameofthe U.S. Government agency and the Governmentcontract numberare:
`
`[pley-\ni>
`BURNS
`BURNS DOAN
`INTELLECTUAL PROPERTY LAW
`IE SWECKER & MATHS LLP
`
`PROVISIONAL APPLICATION FOR PATENT
`COVER SHEET
`
`Page 4
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`-
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`Copy provided by USPTO from the PACR Imaae Datahaaa an nalnaonna
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`al
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`PTO/SB/16 (10-01) (Continuation Sheet)
`Provisional Application for Patent Cover Sheet
`Attorney Docket No.
`033935-005
`Page 2
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`'
`
`Respectfully submitted,
`
`Atty CMa Fini )
`SIGNATURE
`TYPED or PRINTED NAME
`Mary Katherine Baumeister
`
`February4, 2004
`DATE
`Registration No.
`26,254
`(ifappropriate)
`
`Prey=
`BURNS DOANE
`INTELLECTUALPROPERTY LAW
`SWECKER& MATHIS LLP
`
`PROVISIONAL APPLICATION FOR PATENT
`COVER SHEET
`
`Page2
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`__
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`Copy provided by USPTO from the PAGR Imaue Natahaca ne NAInaAR
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`ws
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`ORAL FORMULATIONS OF CLADRIBINE
`
`FIELD OF THE INVENTION
`
`Theiinvention 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.
`—
`
`*
`
`5
`
`BACKGROUND OF THE INVENTION
`Cladribine, which is an acid-labile drug, has the chemical structure as set
`~ forth below:
`i
`:
`
`NH
`
`N
`
`\
`
`rd
`
`
`~S
`
`OH
`
`It is also knownas 2-chloro-2'-deoxyadenosine or 2-CdA. Cladribine exists as a
`white, nonhydroscopic,crystalline powder, consisting of individual crystals and of
`crystalline aggregates.
`Cladribine is an antimetabolite whichhas use in the treatment of
`lymphoproliferative disorders. It has been used totreat experimental leukemias
`such as L1210andclinically for hairy cell leukemia and chronic lymphocytic
`leukemia as well as Waldenstrom's macroglobulinaemia. It has also been usedas
`an immunosuppressive agent and as a modality for the treatmentof a variety of
`
`10
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`15
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`iiss
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`autoimmune conditions saat rheumatoid arthritis, inflammatory bowel sigan .
`(é.g., Crohn's disease, ulcerative colitis) and multiple sclerosis (see e.g., J.
`Liliemark, Clin. Pharmacokinet, 32(2): 120-131, 1997). It has also been - ,
`investigated, either experimentally or clinically in, for example, lymphomas,
`;
`5 Langerhan's cellhistiocytosis, lupus erythematosus, chronic plaque psoriasis,
`Sezary syndrome, Bing-Neel syndrome, recurrent glioma, and solid tumors.
`Oral delivery ofdrugsis often preferred to parenteral delivery for a variety
`ofreasons, foremost patient compliance, or for cost or therapeutic considerations.
`Patient compliance iis enhanced insofar as oral dosageforms alleviate repeated
`10_health care providervisits, or the discomfortof injections or prolonged infusion
`times associated with some active drugs. Ata time of escalating health care costs,
`the reduced costs associated with oral or transmucosal administration versus
`.parenteral administration costs gain importance. Thecost ofparenteral
`administration iis much higher duetothe requirement thata health care
`_ professional administer the cladribine in the health care provider setting, which
`also includes all attendant costsassociated with suchadministration. Furthermore,
`~~in certain instances, therapeuticconsiderations such as the need for a slow release
`of cladribine overa prolonged period oftime may be practically met only by oral
`or transmucosal delivery.
`,
`.
`'. However,to date the oral delivery of cladribine has been plagued by low
`"20
`"bioavailability (see, e.g., J. Liliemark et al., J. Clin. Oncol., 10(10): 1514-1518,
`1992), and suboptimal interpatient variation (see, é.g., J. Liliemark, Clin:
`Pharmacokinet, 32 (2): 120-131, 1997). See also, A. Tarasuik, et al. reporting
`poor absorptionand pH dependent lability (Arch. Immunol. et Therapiae Exper.,
`42: 13-15, 1994),
`7 Cyclodextrins are cyclic oligosaccharides composed ofcyclic a-(1—4)
`linked D-glucopyranose units. Cyclodextrins with six to eight units have been _
`named a.-, B- and y-cyclodextrin, respectively, A numberofderivatives of «-,'B-
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`15
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`and y-cyclodextrin are known in which one or more hydroxyl groupsis/are
`replaced with ether groupsorotherradicals. These compounds are known
`complexing agents and have been previously usedin-thepharmaceutical field to
`form inclusion complexes with Wakeman drugs and to thus’soUEDES them
`
`5
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`10
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`in aqueous media.
`Recently, Schultz et al., 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 problems inherentin previously described aqueous
`" formulations ofcladribine,particularly for subcutaneous and intramuscular |
`injection. Schultz etal. 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 combined with cyclodextrin. The :
`latter finding is taught to be ofparticular benefit in the formulation ofsolid oral.
`dosage forms, where the compound would normally undergo hydrolysis in the acid
`-pH of the stomach contents. Schultz et al. do not appear to have described any
`actual work in connection with solid oral dosage forms. In fact,they describe
`only one method ofpreparing the-solid dosage form, Whichiisa melt extrusion
`process, in whichthe cladribine and cyclodextrin are mixed with other optional |
`additivesand then heated until melting occurs. Furthermore, the broad dosage
`ranges of I mg to 15 mg ofcladribine and 100 mgto 500 mg of cyclodextrin -
`listed in the patent suggest no criticality to the particular amountofcyclodextrinto
`be present with a given amount of cladribine in a solid oral dosage form. Indeed, |
`these dosage ranges include many combinations which may be suitable as mixtures
`_ but not for complex formation. For example,a ratio of 1 mg ofcladribine to 500
`|
`25° mg of cyclodextrin contains too much cyclodextrin, so that the drug would not
`readily leave the complex and achieveits therapeutic function. On the other hand,
`15 mg ofcladribine and only 100 mg of cyclodextrin would not be enough to
`complex that amount ofcladribine.
`
`.
`
`.
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`15
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`~fs
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`;
`
`- The Schultz etal. patent does ‘suggest improving thestability 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 enhancingor maximizing the —
`bioavailability of cladribine from a solid oral dosage form of cladribine and
`cyclodextrin, or a composition specially designed to do so.
`Many workers havestudied the solubility: of specific drugs in water
`’ containing various concentrationsofselected cyclodextrins in order to demonstrate
`"that increasing concentrations of cyclodextrins increase the solubility of the dnigs
`_at selected temperatures and pHlevels, as for example reported in the Schultz
`‘etal. patent. Phase solubility studies havealso been performedby various
`_ workersin orderto elucidate the nature ofthe complex formation, for example,
`whether the cyclodextrin and drug form a 1:1 complex or a 1:2 complex: see, for
`example, Harada et al. U.S. Patent No. 4,497,803,relating to inclusion
`complexesof lankacidin-group antibiotics with cyclodextrin, and Shinoda et al.
`U.S. Patent No. 4,478,995,relating toa complex of an acid addition salt of (2'-
`- benzyloxycarbonyl)pheny] tans-4-guanidinomethyleyclohexanecarborylatewith a
`cyclodextrin.
`While Schultz et al. teach that a cladribine-cyclodextrin complex improves
`_ the water solubility and acid stability ofcladribing, the art does not suggest how to
`. Maximize or enhance the benefits of the complexation in terms of bioavailability
`and interpatient variation when the complex is to be administered iina solid oral
`dosage form.
`,
`
`.
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`5.
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`10
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`15
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`°
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`_
`SUMMARYOF THE INVENTION
`It has now been found that amorphouscyclodextrins can be combined with
`cladribine to form a particularly advantageous product which can be incorporated
`into a solid oral dosage form. This productis a complex cladribine-cyclodextrin
`
`Copy provided by USPTO from the PACR Imaae Datahasa nn naindlonna
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`

`=<
`
`he
`
`complex, and the solid oral dosage form containing it improves oral and/or
`transmucosal bioavailability and/or achieveslower interpatient and/orintrapatient
`variation ofthe drug.
`The present invention provides a pharmaceutical composition comprising a |
`complex cladribine-cyclodextrincomplex which is an intimate amorphous
`admixture of (a) anamorphous inclusion complex ofcladribine with an amorphous
`cyclodextrin and (b) amorphous free cladribineassociated with amorphous
`cyclodextrin as a non-inclusion 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) andthefree cladribine
`. Which forms the non-inclusion complex is amorphous.
`|
`"The invention also provides a method for increasingor enhancing the oral
`bioavailability of cladribine comprising orallyadministering to a subject in need
`- thereof, a pharmaceutical composition comprising a complex cladribine-
`cyclodextrin complex which isan intimate amorphous admixture of(a)an
`_ amorphous inclusion complex of cladribine with an amorphous cyclodextrin and
`- (b) amorphous free cladribine.associated with amorphous cyclodextrin as a non-
`inclusion complex, formulated into a solid oral dosage form which:maximizes the
`amountof cladribine iin the inclusion and non-inclusion complexes.
`4
`The invention further provides for treatment of conditions responsive to
`administration of cladribine in mammals by administering thereto the composition
`ofthe invention, Use of cladribine in thepreparation of the pharmaceutical
`compositionsof the invention is also provided.
`
`)
`
`BRIEF DESCRIPTION OF THE DRAWING
`A more complete appreciation of the invention and its many attendant
`advantages will bereadily understood by reference to the following detailed
`description and the accompanying drawing, wherein the sole Figure is a graphical
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`5
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`representation of the results of a phase solubility study where various molar
`concentrations of hydroxypropyl-f-cyclodextrin (HPBCD)areplotted against
`" various cladribine molar concentrations, with (@) representing the data points
`obtained for complexation under conditions specified iin EXAMPLE2 below.
`
`5
`
`-
`
`.
`
`DETAILED DESCRIPTION OF THE INVENTION.
`*
`Throughout the instantspecification and claims, the followingdefinitionis
`and general statements are applicable.
`Thepatents, published applications, andscientific literature referred to
`herein establish the knowledge ofthose with skill in the art and are hereby —
`incorporated by reference in their entirety to the same extentas ifeach‘was
`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-understooddefinition of a word or phrase anda definition ofthe
`word or phraseas specifically taughtin this specification shall be resolved’in favor
`of the latter.
`‘
`,
`The term "inclusion complex" as used herein refers to a complexof
`cladribine with the selected cyclodextrin wherein the hydrophobicportion 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 ofthe 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
`"
`25_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 ofthe
`cyclodextrin torus(e.g. in the case of hydroxypropy]-B-cyclodextrin,
`
`10 ~
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`15s
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`a
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`hydroxypropyl and hydroxy groups on the glucose rings). This is a more loosely-
`_ held association than an inclusioncomplex,
`.
`As used herein, whetheriina transitional phrase or in.njhe body of a claim,
`" the terms “comprise(s)" and “comprising” are to be interpreted as having an
`open-ended meaning. That jis, the terms-are tobe interpreted synonymously with ~
`the phrases “having at least" or "including at least". When used in the context of
`a process, the term "comprising" means that the process includesat least the .
`recited steps, but may include additional‘Steps. When used in the context of a
`composition, the term "comprising" means that the composition includesat least
`therecited features or components, but may also include additional features or
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`components.
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`-
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`The terms "consists essentially:of" or "consistingessentiallyof" have a
`partially closed meaning,that is, they do notpermit inclusion ofsteps or features
`or components which would substantially change the essential characteristics of a
`15_process or composition; for example, stepsor features or components which
`-
`would significantly interfere with the desired properties ofthe compositions are
`" described herein,i.e., the processor composition is limited to the specified steps
`or materials and those which do not materially affect the basic and novel
`characteristics ofthe’invention. The basic and novelfeatures herein are the
`provision ofa complex cladribine-cyclodextrin complex whichiis an initimate
`amorphous admixture of(a) an amorphousinclusion complex of cladribine withan
`amorphous cyclodextrin and (b) amorphous free 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/or intrapatient variation following administration. Essential to the invention is:
`the combination of the amorphousnature of the Starting cyclodextrin, and the level
`of water solubility exhibited cladribine (about 5 mg/ml at room temperature), and
`consequently its capability for hydrogen bonding, which can be taken advantage of
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`S
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`" g.
`.
`-
`a
`under particular conditions described hereinafter, and which afford a special
`' amorphous mixtureuniquely well-suited for opnyzing tsthe oral DiSavallahality of
`~ cladribine.
`‘
`The terms etal of" and"consists” are closed terminology and allow
`only for the inclusion ofthe recited steps or features or Components.
`Asused herein, the singular forms "a," "an" and "the" specifically also
`“encompass the plural forms of the terms to which they refer, unlessthe content
`clearly dictates otherwise.
`a
`Theterm "about"is used herein to mean approximately, inthe region of,
`
`10~_—sroughly, or around. When the 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
`.
`oy
`"approximately" is used hereinto modify a numerical value above and below the
`stated value by a variance of 20%.
`os
`‘The term "amorphous" is used heréin to refer to a noncrystalline solid.
`’ The cyclodextrins encompassed herein themselves are amorphous because they are
`‘each composed of a multitude of individualisomers, and their complexes with
`cladribine are also amorphous. Further, conditions for complexation canbe
`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 ofthe complex and the cyclodextrin,
`some excess free cladribine does notprecipitate but rather is trapped in amorphous
`form 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 amountofcladribinein the product;
`this additional cladribine, becauseit is amorphous and also becauseit is in
`intimate admixture with the amorphousinclusion complex, is expected to be
`
`15.
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`_somewhat protected from degradation by stomach acid (althoughit may not be as
`-protected as the cladribine which is in the form ofthe inclusion complex).
`The term "saturated" when used in conjunction with a complex of
`__ ¢ladribine in amorphous cyclodextrin means that the complexis saturatedwith
`5—cladribine,thatis, the complex contains the maximum amountof cladribine which
`:
`can be complexed (bymeans ofbothinclusion and non-inclusion complexes) with
`a given amount of cyclodextrin under theconditions of complexation used. A
`phasesolubility study can beused to providethis information, as described in .
`more detail hereinafter.
`(Conditions for the complexation arealso described in
`. 10—moredetail below.) Alternatively, a saturated complex may bearrived at
`‘ empirically by simply adding cladribine to an aqueous solution of the selected
`cyclodextrin until no more cladribine goes into solution: ultimately, excess
`cladribine is removed (byfiltration or centrifugation) and the solution lyophilized
`to provide the dry saturated complex.
`The expression "substantially", asin “substantially free" means within.
`20% ofthe exact calculated amount, preferably within 10%, most preferably
`within 5%.
`-
`The term "interpatient variability" refers to variationamong patients to
`which a drugiis administered. The term “jntrapatient variability" refers to
`20 variation experienced byasingle patient when dosedat different times.
`Asused herein, the recitation of a numerical range for a variableis
`intended to convey that the invention may be practiced with the variable equal to
`any of the values within that range. Thus, for a variable which is inherently
`discrete, the variable can be equal to any integer value of the numerical range,
`includingthe end-points ofthe range. Similarly, for a variable whichis 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
`
`
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`25,
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`“5 .
`
`are inherently discrete, and can be 0.0, 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 includeplural referents
`unless the context clearly dictates otherwise. As used herein, unless specifically
`indicated otherwise, the word "or" is used in the "inclusive" senseof "and/or" and
`not the "exclusive" sense of"either/or."
`Technical and Scientific terms used herein have the meaning commonly
`“understoodby one ofskill in the art to which thepresentinvention pertains, unless
`otherwise defined. . Reference is madeherein to various methodologies and
`10—_materials knownto thoseofskill in the art. Standard reference works setting forth
`the general principles of pharmacology include Goodman and Gilman's The
`Pharmacological Basis ofTherapeutics, 10 Ed., McGraw Hill Companies|Inc.,
`_ New York (2001).
`‘Reference is made hereinafter in detail to specific embodiments of the
`invention. While the invention will be described in conjunction with these specific.
`embodiments,it will be understood that it is not intended to limit the invention to
`such specific embodiments. On the contrary, it is intended to cover alternatives,
`modifications, and equivalents as may be included within the spirit and scope of
`theinvention as defined by the appended claims, In the following description,
`numerousspecific details are set forth in order to provide a thorough
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`— understanding ofthe present invention. The present invention may be practiced
`without someorall of these specific details. In other instances, well-known
`process operations have not been described in detail, in order not to unnecessarily
`obscurethe presentinvention,
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`There is provided by the present invention compositions, as well as
`methods of making andof using pharmaceutical compositions, useful to achieve
`desirable pharmacokinetic properties. Such compositions stem from the discovery
`that solutions of cyclodextrin and cladribine in which cladribineis in a high
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`thermodynamic state, when presented to the gastric mucosa through which they
`" are absorbed are associatédwith improved cladribine absorption, as reflected by
`higher bioavailability and/or lower interpatient variation.
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`It is postulated, without wishing to so limit 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 cladribinesolution in which »
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`cladribineis in the state ofhighest thermodynamicactivity (HTA),thus favoring
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`absorption. Cladribine hasafairly low, although not insignificant, intrinsic
`aqueous solubility; it is in fact somewhat water soluble. Thefree cladribine
`formed from dissociation ofthe inclusion and non-inclusion complexesiina
`‘saturated aqueous solution seeks a morestable activity level by being absorbed.
`through the gastric musoca.
`In view ofthe foregoing,it is apparent that to produce optimal
`. pharmaceutical compositions, in a solid oral dosage form, these dosage forms
`15 should be formulated to release a localized saturated cladribine solution, upon
`" contacl ofthe solid dosage forms with body fluid at the micosa, in which
`~ cladribine is in its HTA state.- To provide such a localized saturated solutionin
`vivo, it is important to first identify the optimal ratio ofcladribine to amorphous
`cyclodextrin, which ratio is referred to herein as the HTA ratio, to be used in the
`20 solid dosage form.
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`The HTAratio is empirically determined andis identified as the ratio of
`cladribine to amorphous cyclodextrin which correspondsto the maximum amount
`of cladribine that can be complexed with a given amount of the cyclodextrin. The
`.HTAratio may be determined using an empirical method such as a phase
`solubility study to determine the saturation concentration of cladribine that can be:
`‘solubilized with different concentrations of amorphous cyclodextrin solutions.
`Hence, the methodidentifies the concentrations at which a saturated cladribine-
`cyclodextrin complex is formed. It is noted that the molar ratio represented by a
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`pointon the phasesolubility graph shows 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 weight ratio. For example,if a
`phase solubility diagramshowsthat 9 moles of a given cyclodextrin are needed to
`maintain the cladribine in a saturated complex, then multiplying the number of
`moles of cladribine by its molecular weight and multiplying the number of moles
`of the selected cyclodextrin by its molecular weight, one can arriveatthe ratio of
`the products as an appropriate optimized weight ratio, A phase solubility Study
`also provides information about the nature ofthe cladribine-cyclodextrin inclusion —
`complex formed, for example whether the inclusion complex is a 1:1 complex (1
`molecule ofdrug complexed with 1 molecule ofcyclodextrin) or a 1:2 complex (1
`molecule of drug complexed with 2 molecules of cyclodextrin).
`In accordance with the present invention,one can start using either the
`selected amorphous cyclodextrin, such as hydroxypropyl--B-cyclodextrin (HPBCD)
`or hydroxypropyl-y-cyclodextrin, or cladribine as the fixed variable to which an
`excess ofthe other is added to identify various solubility datapoints (indicating
`saturated cladribine-cyclodextrin complexes) and draw theresultant line.
`Typically, cladribine is added to an aqueous solution having a known
`concentration of amorphous cyclodextrin under conditions empirically found to
`promote complex formation. Generally, the complexation is conducted with
`heating, for exampleat 45 to 60°C fora significant period of time, #: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. Excess precipitated cladribineis then removed
`andthe cladribine concentration is subsequently measured. This concentration
`represents the amountof cladribine solubilized for a given amorphouscyclodextrin
`concentration. This process is repeated for a different known concentration of
`cyclodextrin until several data points are obtained. Each data pointrepresents the
`concentration of the cladribine dissolved in a known concentration ofthe selected
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`amorphous eytiodenttin, The data points are then plotted to show the
`concentration ofcladribine against the various cyclodextrin concentrations used.
`Thegraph is a phase solubility diagram which can beused to determine the
`amountof cladribine for any specific concentration of cyclodextrin used to form
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`>__the solution under a given set of complexation conditions. It will be appreciated
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`thatthe aqueoussolubility of Cladribine is about 5 mg/ml at room temperature and
`" would be higher at elevated temperature. Consequently, the data‘points
`correspondto’the amountofcladribine dissolved in aqueous HPBCDorother
`amorphous cyclodextrin under the selected conditions; when later lyophilized, the
`solution yields a couple cladribine-cyclodextrin complex which is an intimate
`amorphous admixture of (a) anamorphous inclusion complex of cladribine with an
`amorphous cyclodextrinand(b) amorphousfree cladribine associated with
`amorphous cyclodextrin as a non-inclusion complex. If equilibrium conditions are
`reached duringthe complexation, the amorphous cladribine-cyclodextrin complex
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`15_will be saturated with cladribine. ‘ ‘
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`One ofskill in the art will appreciate that concentrations at which saturated
`complexes of cladribine with amorphouscyclodextrins are formed (and thus HTA
`ratios as well) may be identified by a variety of alternative methodologies.
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`Accordingly, any method knownin thefield suitableto identify these -
`concentrations is within the scope ofthe invention.
`Using intrinsically amorphouscyclodextrins, for example hydroxypropy]-
`B-cyclodextrin, hydroxypropyl-y-cyclodextrin, randomly methylated
`cyclodextrins, and the like, with cladribine, which is a somewhat water soluble ”
`compound (capable of H-bonding through its free hydroxy and amino groups), the
`25__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 actually inclusion complexed
`material. Consequently, it is possible to maximize the cladribine in solid
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`amorphous mixtures, by forcing additional cladribineinto solution (using more
`dilute solutions ofcyclodextrin, higher temperatures and longercomplexation
`times, as indicated above). When the solution is cooled off, the extensively
`amorphous nature of these cyclodextrins does not allow crystallization ofan
`excess amount ofcladribine beyond that which forms an inclusion complex with
`the cyclodextrin; and upon freeze-drying/lyophilization, one obtains an amorphous
`mixture of cladribine-“cyclodextrin inclusion complex (which is amorphous) and
`‘ amorphousfree cladribine, loosely associated with uncomplexed cyclodextrin (and
`even with complexed cyclodextrin) by hydrogen-bonding, that is the non-inclusion.
`complex. Thisis done by maximizing solubilization by elevating the temperature
`- . (for example, to about 50° to 80°C), and stirring for many hours(up to 24 hours)
`before freeze-drying. The apparent optimum weight/weightratio is about 1:14 of
`cladribine:cyclodextrin. If too much excess cladribine is added to the
`complexation medium, then crystallization of someof the cladribine takes place,
`which wouldin turnresult in somecrystalline cladribine in the product; this
`undesired excess cladribineis notin solution and is not H-bonded to the
`’ amorphous cyclodextrin and lowers the weight ratio.