`
`RECD 26 JUL 2004
`
`United States Patent and Trademark Office
`
`June 03, 2004
`
`THIS IS TO CERTIFY THAT ANNEXED HERETO IS A TRUE COPY FROM
`THE RECORDS OF THE UNITED STATES PATENT AND TRADEMARK
`OFFICE OF THOSE PAPERS OF THE BELOW IDENTIFIED PATENT
`APPLICATION THAT MET THE REQUIREMENTS TO BE GRANTED A
`FILING DATE UNDER35 USC 111.
`ysfot]
`9387-
`vs/a4} 93
`APPLICATIONNUMBER: 60/541,247
`
`FILING DATE: February 04, 2004
`
`I
`.
`‘PRIORITY DOCUMENT
`SUBMITTED OR TRANSMITTEDIN
`COMPLIANCE WITH
`RULE 17.1(a) OR (b)
`
`|
`
`|
`|
`
`
`
`
`
`
`
`
`
`
`aE
`i : :
`Ue
`,
`|)
`{|
`
`oh
`a
`Ay
`A :
`ne
`ue
`
`EH
`
`
`
`
` eS———
`
`
`
`PA 1178182
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`i
`= =
`
`
`
`
`LOALE,TOWHOMTHESE; PRESENTS; SHATT:,COME:
`UNITED STATES DEPARTMENT OF COMMERCE
`
`
`
`
`COMMISSIONER OF PATENTS AND TRADEMARKS
`
`
`
`: "
`By Authority of the
`UH
`
`
`
`oy
`
`spawn L
`
`J
`
`
`
`
`
`
`Certifying Officer
`MERCK2046
`HOPEWELL v MERCK
`
`
`IPR2023-00481
`
`MERCK 2046
`HOPEWELL v MERCK
`IPR2023-00481
`
`

`

`PATENT APPLICATION SERIAL NO. —_—__——
`
`U.S. DEPARTMENT OF COMMERCE
`PATENT AND TRADEMARK OFFICE
`
`FEE RECORD SHEETSREREAURYSHEET
`
`02/09/2004 FHETEKI! 00000018 60541247
`01 FCs1005
`160.00 OP
`
`PTO-1556
`(5/87)
`
`“U.S. Govemment Printing Office: 2001 — 481-697/59173
`
`Copy provided by USPTO from the PACH Imade Natahana n= fainalonna
`
`

`

`182thwy
`
`—
`© Customer Number 21839
`3
`Oo
`
`PTOISB/16 (10-04PN
`Approvedforuse through 10/31/2002. OMB 0651-00372
`Patent and Trademark Office; U.S. DEPARTMENT OFCOMMERCEG}A
`se
`of
`
`22N
`
`PROVISIONAL APPLICATION FOR PATENT COVER SHEET
`This is a requestfor filing a PROVISIONAL APPLICATION FOR PATENTunder37 C.F.R. § 1.53(c).
`
`Docket
`Type a plus sign
`
`
`Number 033935-005|(+) inside this box| *
`
`
`INVENTOR(s)/APPLICANT(s)
`
`RESIDENCE(CITY AND EITHER STATE OR
`
`BODOR
`
`Ss.
`
`ORAL FORMULATIONS OF CLADRIBINE
`
`
`
`oe
`
`
`
`
`10101 Colllins Avenue, #4A
`Bal Harbour, Florida 33154
`
`
`
`
`
`
`
`CO Additional inventors are being named onthe ___separately numbered sheets attached hereto.
`
`TITLE OF THE INVENTION (500 characters max)
`.
`
`CORRESPONDENCE ADDRESS
`Burns, Doane, Swecker & Mathis, L.L.P.
`
`Customer Number 21839
`Post Office Box 1404
`
`
`Alexandria
`
`
`
`United States of
`
`
`ENCLOSED APPLICATION PARTS (checkall that apply)
`
`I Specification Number ofPages.
`. & Other(specify) Claims 4-45 (7pgs.), Abstract(1
`
`28
`
`
`[%] Drawing(s)—_Nurhber of Sheets 1
`.
`Pg.)
`°
`
`
`‘TH Application Data Sheet, See 37 CFR 1.76
`
`
`
`
`
`
`METHOD OF PAYMENTOFFILING FEES FOR THIS PROVISIONAL APPLICATION FOR PATENT (check one)
`(1 Applicant claims small entity status. See 37 C.F.R. § 1.27.
`x] Acheck or money orderis enclosed to cover the Provisional
`filing fees.
`I The Directoris hereby authorized to charge any deficiencyin
`filing fees or credit any overpaymentto Deposit Account No.
`02-4800. This paperi$ submitted in duplicate.
`.
`a
`Theinvention was made by an agency ofthe United States Governmentor under a contract with an agencyof the United States Government.
`[x] No.
`1 Yes, the nameof the U.S, Govamment agency and the Government contract numberare:
`
`
`$80.00 (2005)
`C]
`
`
`PROVISIONAL
`
`
`FILING FEE
`
`
`
`&]
`AMOUNT(S)
`
`
`
`
`
`$160.00 (1005)
`
`
`
`DOANE
`INTELLECTUAL PROPERTY LAI
`BURNS DOANE SWECKER & RAATHISLLP
`
`PROVISIONAL APPLICATION FOR PATENT
`COVER SHEET
`
`Page1
`
`Copy provided by USPTO from the PAGR Image Datahaaa an neina mana
`
`

`

`of
`
`fn
`
`a
`
`PTO/SB/16 (10-01) (Continuation Sheet)
`Provisional Application for Patent Cover Sheet
`Attorney Docket No.
`033935-005
`Page 2
`
`'
`
`Respectfully submitted,
`
`NAy i Henee bs seonee ha )
`SIGNATURE
`TYPEDor PRINTED NAME
`Mary Katherine Baumeister
`
`February4, 2004
`DATE
`Registration No.
`26,254
`(if appropriate)
`
`DOANE
`BURNS DOANE
`INTELLECTUAL PROPERTY LAW
`SWECKER & MATHIS LLP
`
`PROVISIONAL APPLICATION FOR PATENT
`COVER SHEET
`
`Page 2
`
`Copy provided by USPTO from the PACR Image Natahaca ne aint anna
`
`

`

`-1-
`
`ORAL FORMULATIONS OF CLADRIBINE
`t
`
`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 structureas set
`~ forth below:
`‘
`
`NH) ~
`
`
`
`It is also known as 2-chloro-2'-deoxyadenosine or 2-CdA. Cladribine exists asa
`10° white, nonhydroscopic, crystalline powder, consisting of individual crystals and of
`crystalline aggregates.
`Cladribineis an antimetabolite which hasuse in the treatment of
`lymphoproliferative disorders. It has been usedtotreat experimental] leukemias
`such as L1210 and clinically for hairy cell leakemia and chronic lymphocytic
`leukemia as well as Waldenstrom's macroglobulinaemia.
`It has also been used as
`an immunosuppressive agent and as a modality for the treatment of a variety of
`
`15
`zp
`
`Copy provided by USPTO from the PAGR Image Database on nantanna
`
`

`

`-2--
`
`_
`
`autoimmune conditions including rheumatoid arthritis, inflammatory bowel disease .
`(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 ofdrugs is often preferred to parenteral delivery for a variety
`of reasons, foremost patient compliance, or for cost or therapeutic considerations.
`Patient complianceiis enhanced insofar as oral dosage:forms alleviate repeated
`10_health care provider visits, or the discomfortof injections or prolonged infusion
`, times associated with someactive 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 providersetting, which
`also includes all attendant costsassociated with suchadministration. Furthermore,
`'~ in certain instances, therapeuticconsiderations such as the need for a slow release
`ofcladribine over a prolonged period oftime may be practically met only byoral
`or transmucosal delivery.
`,
`.
`'. 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 suboptimal interpatient variation (see, ¢.g., J. Liliemark, Clin:
`Pharmacokinet, 32 (2):120-131, 1997). See also, A. Tarasuik, etal. reporting
`poor absorptionand pH dependent lability (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 been |
`named o.-, B- and y-cyclodextrin, respectively. A numberof derivatives of a-, B-
`
`"20
`'
`
`,
`
`.
`
`.
`
`|
`
`15
`
`25
`
`Copy provided by USPTO from the PAGR Imaae Dalahane an NANTOAAA
`
`

`

`.
`
`|
`
`10
`
`15.
`
`-
`
`+
`
`.
`
`5_in aqueous media.
`Recently, Schultz ef 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 inherent in previously described aqueous
`" formulations ofcladribine,particularly for subcutaneous and intramuscular
`injection. Schultz et al. have found that cladribine is not only significantly more
`soluble in aqueous media when formulated with cyclodextrin, but also iis 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 ofthe 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 methodofpreparing 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 1 mg to 15 mg of cladribine and 100 mgto 500 mg of cyclodextrin -
`listed in the patent suggest no criticality to the particular amountofcyclodextrin’to
`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. mgof cladribine to 500
`|
`25 ° mg of cyclodextrin contains too much cyclodextrin, so that the drug would not
`readily leave the complex and achieve its therapeutic function. On the other hand,
`15 mg of cladribine and only 100 mg of cyclodextrin would not be enoughto
`complex that amount ofcladribine.
`
`’ 20
`,
`
`-3-
`
`and y-cyclodextrin are known in which one or more hydroxyl groupsis/are
`replaced with ether groupsor other radicals, These compounds are known
`complexing agents and have been previously usedin.the pharmaceutical field to
`form inclusion complexes with water-insoluble drugs and to thus:solubilize them
`
`Copy provided by USPTO from the PAGR Imave Databane on NAINT/OANA
`
`

`

`4.
`
`.
`
`cyclodextrin.
`
`,
`
`- The Schultz etal. patentdoessuggest improving the stability ofcladribine
`in oral dosage forms by combining/complexing it with cyclodextrin, but does not
`suggest improvingthe drug's oral bioavailability by such means; in fact, the patent
`does not describe or suggest a method for enhancingor maximizing the
`5 bioavailability of cladribine from a solid oral dosage form of cladribine and
`cyclodextrin, or a composition specially designed to do so.
`Manyworkers have studied 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 drigs
`at selected temperatures and pHlevels, as for example reported in the Schultz
`et al. patent. Phase solubility studies have also been performed by various
`_ Workers in 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
`complexes of lankacidin-group antibiotics with cyclodextrin, and Shinoda et al.
`U.S. Patent No. 4,478,995, relating to a complexof an acid addition salt of (2'-
`benzyloxycarbonyl)phenyl trans-4-guanidinomethyleyclohexanecarboxylatewith a
`While Schultz et al. teach that a cladribine-cyclodextrin compleximproves
`_ the watersolubility 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 administerediin a solid oral
`dosage form.
`
`10
`
`15
`
`°
`
`-
`
`.
`
`. 20
`
`-
`
`25
`
`_
`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 product is a complex cladribine-cyclodextrin
`
`Copy provided by USPTO from the PACR Imaae Datahase nn AAINA nna
`
`

`

`-5-
`
`complex, andthe solid oral dosage form containingit improves oral and/or
`transmucosal bioavailability and/or achievesowerinterpatient and/or intrapatient a,
`variation ofthe drug.
`.
`The present invention provides a pharmaceutical composition comprising a |
`complex cladribine-cyclodextrincomplex whichis an intimate amorphous
`admixture of (a) anamorphous inclusion complex of cladribine with an amorphous
`cyclodextrin and (b) amorphousfree 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) and the free cladribine
`. Which forms thé non-inclusion complexis 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 whichisan intimate amorphous admixture of (a) an
`_ amorphousinclusion 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 whichmaximizes the
`amountof cladribineiin the inclusion and non-inclusion complexes.
`,
`The invention furtherprovides for treatment of conditions responsive to
`administration of cladribine iIn mammals by administering thereto the composition
`ofthe invention. Useof cladribine in thepreparation ofthe pharmaceutical
`compositions ofthe inventionis 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
`
`3
`
`10 :
`
`15
`
`20.
`,
`
`25
`
`Copy provided by USPTO from the PACR Imaae Database on 06/1 9nna
`
`

`

`6
`
`Tepresentation of the results of a phase solubility study where various molar
`concentrations of hydroxypropyl-B-cyclodextrin (HPBCD)are: plotted against
`" various cladribine molar concentrations, with (@) representing the data points
`obtained for complexation underconditions specified in EXAMPLE2 below.
`
`10 ~
`
`5 mS DETAILED DESCRIPTION OF THE INVENTION oo
`Throughout the instant.specification and claims, the followingdefinitions
`and general statements are applicable.
`The patents, 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 extent as if each was
`specifically and individually indicated to be incorporated by reference. Any
`conflict between any reference cited herein and the specific teachings ofthis
`" Specification shall be resolved in favor of the latter. Likewise, any conflict
`between an art-understood definition of a word or phrase anda definition of the
`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 complex.of
`cladribine with the selected cyclodextrin wherein the hydrophobic portion ofthe
`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 which is 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 ofthe 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,
`
`15°
`
`20
`
`Copy provided by USPTO from the PACR Imaue Datahasa an agingRae
`
`

`

`-7-
`
`hydroxypropyl and hydroxy groups on the glucose rings). This is a more loosely-
`_ held association than an inclusioncomplex,
`|
`the body ofa claim,
`As used herein, whetheriina transitional phrase or inn
`" the terms “comprise(s)" and “comprising” are to be interpreted as having an
`open-ended meaning. That jis, the terms-are to be interpreted synonymously with -
`the phrases “having at least" or "including at least". Whenused in the context of
`a process, the term "comprising" means that the process includesat least the |
`recited steps, but may include additionalSteps. Whenused 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
`components.
`.
`The terms "consists essentially:of" or "consistingessentiallyof" have a
`partially closed meaning, that is, they do not permit inclusion ofsteps or features
`or components which would substantially change the essential characteristics of a
`process or composition; for example, stepsor features or components which
`would significantly interfere with the desired properties ofthe compositions are
`describedherein,i.é., 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) 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 lower interpatient |
`and/or intrapatient variation following administration. Essential to the inventionis-
`the combination of the amorphous nature 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
`
`5
`
`10 |
`
`15
`-
`
`20
`
`25
`
`7
`
`Copy provided by USPTO from the PAGR Image Database nn ARini nna
`
`—
`
`

`

`"8
`
`|
`
`7
`
`a
`
`. 5
`
`15
`
`° under particular conditions described hereinafter, and which afford a special
`’ amorphous mixtureuniquely well-suited for optimizing the oral bioavailability of
`~ cladribine.
`The terms "consists of" and“consists”are closed terminology and allow
`only forthe inclusion ofthe recited steps or features or components.
`As used 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.
`The term "about" is used herein to mean approximately, inthe region of,
`10—sroughly, 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
`| 4
`"approximately" is used herein to modify a numerical value above and below the
`stated value by a variance of 20%.
`a
`~The term “amorphous”is used heréinto 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 ofthe amorphous nature ofthe complex and the cyclodextrin,
`some excess free cladribine does notprecipitate butrather is trapped in amorphous
`form iin 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 amount of cladribine in the product;
`this additional cladribine, because it is amorphous and also becauseit is in
`intimate admixture with the amorphousinclusion complex, is expected to be
`
`20
`
`.
`
`. 25
`
`Copy provided by USPTO from the PACR Imaae Datahaca nn ARIMA MARA
`
`—
`
`

`

`5 .
`
`_somewhat protected from degradation by stomach acid (although it may not be as
`-protected as the cladribine whichis in the form of the inclusion complex).
`The term "saturated" when used in conjunction with a complexof
`cladribine in amorphous cyclodextrin means that the complex is saturated with .
`cladribine,thatis, the complex contains themaximum amount ofcladribine which
`can be complexed (bymeans of both inclusion and non-inclusion complexes) with
`a given amount of cyclodextrin under theconditions of complexation used. A
`phasesolubility study can be used to provide this information, as described in |
`more detail hereinafter.
`(Conditions for the complexation arealso described in
`moredetail below.) Alternatively, a saturated complex may be arrivedat
`10
`"* empirically by simply adding cladribine to an aqueous solution oftlie selected
`cyclodextrin until no more cladribine goes into solution; ultimately, excess
`cladribine is removed (byfiltration or centrifugation) and the solution lyophilized
`to provide the drysaturated complex.
`|
`The expression "substantially", asin “substantially free" means within
`20% of the 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 “intrapatient variability" refers to
`variation éxperienced by a single patient when dosedat different times.
`Asused herein, the recitation ofa numerical range for a variable is
`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,
`including the end-points ofthe range. Similarly, for a 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
`
`20
`
`25,
`
`15
`
`-9-
`
`Copy provided by USPTO from the PACR Imaue Database an Naina enna
`
`

`

`-10-
`
`10
`
`15.
`.
`
`a) .
`
`are inherently discrete, and can be 0.0, 0.1, 0.01, 0.001, or any otherreal 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" 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
`materials knownto thoseofskill in the art. Standard reference works setting forth
`the general principles ofpharmacology 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. Onthe 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 appendedclaims.
`In the following description,
`numerousspecific details are set forth in order to provide a thorough
`.
`20
`an understanding of the 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
`obscure the present invention,
`.
`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 which cladribineis in a high
`
`25
`
`Copy provided by USPTO from the PACR Imaae Databana an ARINAOARA
`
`

`

`-11-
`
`10
`
`.
`
`,
`
`15°
`
`thermodynamic state, when presented to the gastric mucosa through which they
`’ are absorbed are associatedwith improved cladribine absorption, as Teflected by
`higher bioavailability and/or lowerinterpatient variation.
`oo
`It is postulated, without wishing to so limit the invention,that upon
`5__dissolution (e.g., by contact with a fluid, such as a bodily fluid), dry compositions -
`i, - according to the invention formalocally saturated cladribinesolution in which-
`
`.
`cladribine is in the state of highest thermodynamic activity (HTA), thus favoring
`absorption. Cladribine has a fairly low, although not insignificant, intrinsic
`aqueous solubility; it is in fact somewhat water soluble. The free cladribine
`formed from dissociation of the inclusion and non-inclusion complexesiina
`‘saturated aqueous solution seeks a morestable activity level by being absorbed -
`through the gastric musoca.
`In view of the 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 body fluid at the mucosa, in which
`~ cladribineis in its HTA state.- To provide such a localized saturated solittion in
`vivo, it is important to first identify the optimal ratio ofcladribine to amorphous
`cyclodextrin, which ratio is referred to herein as the HTAratio, to be used in the
`20 solid dosage form.
`.
`.
`The HTA ratio is empirically determined andis identified as the ratio of
`cladribine to amorphous cyclodextrin which corresponds to the maximum amount
`of cladribine that can be complexed with a given amountofthe 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 amorphouscyclodextrin solutions.
`Hence, the method identifies the concentrations at which a saturated cladribine-
`cyclodextrin complex is formed.
`It is noted that the molar ratio represented by a
`
`"25
`|
`
`:
`
`,
`
`|
`
`|
`
`Copy provided by USPTO from the PAGR Image Database on naint/onna
`
`

`

`-12-
`
`pointon the phase solubility graph shows how many moles of amorphous
`cyclodextrin are the minimum needed to maintain the drug inthe complex, under
`given conditions; this may then be converted toa weight ratio. For example,if a
`phase solubility diagramshowsthat 9 molesof 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 arrive at the ratio of
`the products as an appropriate optimized weight ratio. A phase solubility study
`also provides information about the nature of the cladribine-cyclodextrin inclusion
`complex formed, for example whether the 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 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 data points (indicating
`saturated cladribine-~cyclodextrin complexes) and draw the resultant 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 example at 45 to 60°C fora significant period of 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. Excess precipitated cladribineis then removed
`andthe cladribine concentration is subsequently measured. This concentration
`represents the amount of cladribine solubilized for a given amorphous cyclodextrin
`concentration. This process is 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 concentration of the selected
`
`—-
`
`10
`
`15
`
`20
`
`25
`
`
`
` Copyprovided by USPTOfrom the PAGR Imara Netohaca a= ASTANA
`
`

`

`-13-
`
`amorphous cyclodextrin The data points are then plotted to show the
`concentration 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 _
`5__the solution under a given set of complexation conditions. It will be appreciated
`,
`thatthe aqueoussolubility of cladribine is about 5 mg/ml at room temperature and
`" would be higherat elevated temperature. Consequently, thedata‘points
`correspondtothe amountof cladribine dissolved in aqueous HPBCDorother
`amorphous cyclodextrinunder the selectedconditions; when later lyophilized, the
`10__solution yields 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. If equilibrium conditions are
`reached duringthe complexation, the amorphous cladribine-cyclodextrin complex
`will be saturated with cladribine.
`.
`‘
`Oneofskill in the art will appreciate that concentrations at which saturated
`complexes of cladribine with amorphouscyclodextrins are formed (and thus HTA
`, ratios a$ well) may be identified bya variety of alternative methodologies.
`-
`Accordingly, any method knownin thefield suitable to identify these -
`concentrations is within the scope ofthe invention.
`Using intrinsically amorphouscyclodextrins, for example hydroxypropy]-
`B-cyclodextrin, hydroxypropyl-y-cyclodextrin, randomly methylated
`cyclodextrins, andthelike, with cladribine, which is a somewhat water soluble ”
`compound (capable of H-bonding through its free hydroxy and amino groups), the
`cladribine provides increased solubility in solutions of these cyclodextrins. Not
`only is there increased water solubility but also H-bonded association ofthe
`cladribine with the cyclodextrin, separately from the actually inclusion complexed
`material. Consequently, it is possible to maximize the cladribine in solid
`
`20
`
`25
`
`Copy provided by USPTO from the PAGR Image Databasa on Naini enna
`
`15
`
`|
`
`|
`
`

`

`-14-
`
`|
`
`’
`
`amorphous mixtures, by forcing additional cladribineinto solution (using more
`dilute solutions ofcyclodextrin, higher temperatures and longer complexation
`times, as indicated above). When the solution is cooled off, the extensively
`amorphous nature of these cyclodextrins does not allow crystallization of an
`excess amountofcladribine beyondthat 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. This is done by maximizing solubilization by elevating the temperature
`- . (for example, to about 50° to 80°C), and stirring formany hours(up to 24 hours)
`before freeze--drying. The apparent optimum weight/weight ratio 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 would in turnresult in somecrystalline cladribine in the product; this
`undesired excess cladribineis notin solution and is not H-bondedto the
`* amorphous cyclodextrin and lowers the weight ratio. Therefore,it is desirableto.
`carefully contro] the amountof excess cladribine beyond that which will form the
`‘inclusion complex to only the amount which will dissolve in the solution. The
`desired amorphous mixture of amorphous inclusion complex and amorphous free
`cladribine can be termeda “complex cladribine-cyclodextrin complex," which
`includes both inclusion and non-inclusion/H-bonded complexes. The inclusion
`complex is a complex of cladribine inserted into the hydrophobiccavity ofthe
`selected amorphous cyclodextrin, while the non-inclusion/H-bonded complex is
`-amorphousfree cladribine loosely hydrogen-bonded to the cyclodextrin.
`In. the
`case of a