`US008785415B2
`
`c12) United States Patent
`Bodor et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,785,415 B2
`*Jul. 22, 2014
`
`(54) ORAL FORMULATIONS OF CLADRIBINE
`
`FOREIGN PATENT DOCUMENTS
`
`(75)
`
`Inventors: Nicholas S. Bodor, Bal Harbour, FL
`(US); Yogesh Dandiker, Toronto (CA)
`
`(73) Assignee: Ares Trading S.A., Aubonne (CH)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 357 days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 12/986,310
`
`(22) Filed:
`
`Jan.7,2011
`
`(65)
`
`Prior Publication Data
`
`US 2011/0097306 Al
`
`Apr. 28, 2011
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 10/551,205, filed as
`application No. PCT/US2004/009387 on Mar. 26,
`2004, now Pat. No. 7,888,328.
`
`(60) Provisional application No. 60/458,922, filed on Mar.
`28, 2003, provisional application No. 61/484,756,
`filed on Jul. 2, 2003, provisional application No.
`60/541,247, filed on Feb. 4, 2004.
`
`(51)
`
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 3117076
`A61K 47140
`(52) U.S. Cl.
`USPC ............................................... 514/46; 514/58
`( 58) Field of Classification Search
`CPC .............. A61K 31/7076; A61K 47/40; A61K
`47/48969
`USPC ...................................................... 514/46, 58
`See application file for complete search history.
`
`(56)
`
`References Cited
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`
`(Continued)
`
`Primary Examiner - Shaojia Anna Jiang
`Jonathan S Lau
`Assistant Examiner -
`(74) Attorney, Agent, or Firm - Dentons US LLP
`
`(57)
`
`ABSTRACT
`
`Provided are compositions of cladribine and cyclodextrin
`which are especially suited for the oral administration of
`cladribine.
`
`79 Claims, 1 Drawing Sheet
`
`MERCK 2029
`HOPEWELL v MERCK
`IPR2023-00481
`
`
`
`US 8,785,415 B2
`Page 2
`
`(56)
`
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`International Search Report dated Oct. 12, 2004 for PCT/US2004/
`009387, filed Mar. 26, 2004.
`PCT International Preliminary Report on Patentability and Written
`Opinion for International Application No. PCT/US2004/009387,
`International Filing date Mar. 26, 2004.
`
`* cited by examiner
`
`
`
`U.S. Patent
`U.S. Patent
`
`Jul. 22, 2014
`Jul. 22, 2014
`
`US 8,785,415 B2
`US 8,785,415 B2
`
`
`
`
`
`Cladribineconc.(M)
`
`Si'
`; o.o5o
`0.050
`C
`0
`C,
`0.040
`~ 0.040
`:ci
`·c:
`'g 0.030
`0.030
`u
`
`0.080
`0.080
`
`0.070
`0.070
`
`0.060
`0.060
`
`0.020
`0.020
`
`0.010
`0.010
`
`0.000 . . i - - - -~ - - - - - - - - - - - - - - - - - -
`0.000
`0.150
`0.200
`0.250
`0.300
`0.000
`0.050
`0.100
`0.000
`0.050
`0.100
`0.150
`0.200
`0.250
`0.300
`CD cone. (M)
`CD conc.(M)
`
`
`
`US 8,785,415 B2
`
`1
`ORAL FORMULATIONS OF CLADRIBINE
`
`CROSS-REFERENCE TO EARLIER
`APPLICATIONS
`
`This application is a continuation of prior U.S application
`Ser. No. 10/551,205 filed Nov. 14, 2006, now U.S. Pat. No.
`7,888,328, which is the US national stage of International
`Application No. PCT/US2004/009387, filed Mar. 26, 2004,
`which claims benefit under 35 U.S.C. §119(e) ofU.S Provi(cid:173)
`sional Application No. 60/458,922, filed Mar. 28, 2003; of
`U.S Provisional Application No. 60/484,756, filed Jul. 2,
`2003; and of U.S Provisional Application No. 60/541,247,
`filed Feb. 4, 2004, all of said applications being hereby incor(cid:173)
`porated by reference herein in their entireties and relied upon.
`
`BACKGROUND OF THE INVENTION
`
`Cladribine, which is an acid-labile drug, has the chemical
`structure as set forth below:
`
`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.
`Cladribine is an antimetabolite which has use in the treat(cid:173)
`ment of lymphoproliferative disorders. It has been used to
`treat experimental leukemias such as L1210 and clinically for
`hairy cell leukemia 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 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, 32(2): 120-131, 1997).
`It has also been investigated, either experimentally or clini(cid:173)
`cally in, for example, lymphomas, Langerhan's cell histiocy(cid:173)
`tosis, lupus erythematosus, chronic plaque psoriasis, Sezary
`syndrome, Bing-Neel syndrome, recurrent glioma, and solid
`tumors.
`Oral delivery of drugs is often preferred to parenteral deliv(cid:173)
`ery 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 provider visits, or the discomfort of injections or
`prolonged infusion times associated with some active drugs.
`At a time of escalating health care costs, the reduced costs
`associated with oral administration versus parenteral admin(cid:173)
`istration costs gain importance. The cast of parenteral admin(cid:173)
`istration is much higher due to the requirement that a health
`care professional administer the cladribine in the health care
`provider setting, which also includes all attendant costs asso(cid:173)
`ciated with such administration. Furthermore, in certain
`
`2
`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 transmucosal delivery.
`However, to date the oral delivery of cladribine has been
`5 plagued by low bioavailability (see, e.g., J. Liliemark at al., J.
`Clin. Oneal., 10(10): 1514-1518, 1992), and suboptimal
`interpatient variation (see, e.g., J. Liliemark, Clin. Pharma(cid:173)
`cokinet, 32 (2): 120-131, 1997). See also, A. Tarasuik, et al.
`reporting poor absorption and pH dependent !ability (Arch.
`10 Immunol. et Therapiae Exper., 42: 13-15, 1994).
`Cyclodextrins are cyclic oligosaccharides composed of
`cyclic a-(1-4) liuked D-glucopyranose units. Cyclodextrins
`with six to eight units have been named a-, ~- and y-cyclo(cid:173)
`dextrin, respectively. The number of units determines the size
`15 of the cone-shaped cavity which characterizes cyclodextrins
`and into which drugs may be included to form stable com(cid:173)
`plexes. A number of derivatives of a-, ~- and y-cyclodextrin
`are known in which one or more hydroxyl groups is/are
`replaced with ether groups or other radicals. These com-
`20 pounds are thus known complexing agents and have been
`previously used in the pharmaceutical field to form inclusion
`complexes with water-insoluble drugs and to thus solubilize
`them in aqueous media.
`Recently, Schultz eta!., in U.S. Pat. No. 6,194,395 Bl,have
`25 described complexing and solubilizing cladribine with cyclo(cid:173)
`dextrin. The Schultz et al. patent primarily addresses the
`problems inherent in previously described aqueous formula(cid:173)
`tions of cladribine, particularly for subcutaneous and intra(cid:173)
`muscular injection. Schultz et al. have found that cladribine is
`30 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 of particular benefit in the
`formulation of solid oral dosage forms, where the compound
`35 would normally undergo hydrolysis in the acid pH of the
`stomach contents. Schultz at al. do not appear to have
`described any actual work in connection with solid oral dos(cid:173)
`age forms. In fact, they describe only one method of preparing
`the solid dosage form, which is a melt extrusion process, in
`40 which the cladribine and cyclodextrin are mixed with other
`optional additives and then heated until melting occurs. Fur(cid:173)
`thermore, the broad dosage ranges of 1 mg to 15 mg of
`cladribine and 100 mg to 500 mg of cyclodextrin listed in the
`patent suggest no criticality to the particular amount of cyclo-
`45 dextrin 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 mg of
`cladribine to 500 mg of cyclodextrin contains too much
`50 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 enough to complex that amount of cladribine.
`The Schultz et al., patent does suggest improving the sta-
`55 bility of cladribine in oral dosage forms by combining/com(cid:173)
`plexing it with cyclodextrin, but does not suggest improving
`the drug's oral bioavailability by such means; in fact, the
`patent does not describe or suggest a method for enhancing or
`maximizing the bioavailability of cladribine from a solid oral
`60 dosage form of cladribine and cyclodextrin, or a composition
`specially designed to do so.
`Many workers have studied the solubility of specific drugs
`in water containing various concentrations of selected cyclo(cid:173)
`dextrins in order to demonstrate that increasing concentra-
`65 tions of cyclodextrins increase the solubility of the drugs at
`selected temperatures and pH levels, as for example reported
`in the Schultz et al. patent. Phase solubility studies have also
`
`
`
`US 8,785,415 B2
`
`3
`been performed by various workers in order to 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 al. U.S. Pat. No. 4,497,803, relat(cid:173)
`ing to inclusion complexes of lankacidin-group antibiotics
`withcyclodextrin, and Shinoda eta!. U.S. Pat. No. 4,478,995,
`relating to a complex of an acid addition salt of (2'-benzy(cid:173)
`loxycarbonyl)phenyl
`trans-4-guanidinomethylcyclohexan(cid:173)
`ecarboxylate with a cyclodextrin.
`While Schultz et al. teach that a cladribine-cyclodextrin 10
`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 terms ofbioavail(cid:173)
`ability and interpatient variation when the complex is to be 15
`administered in a solid oral dosage form.
`
`4
`In yet a further aspect the invention provides a pharmaceu(cid:173)
`tical composition obtainable by a process comprising the
`steps of:
`(i) combining cladribine and an amorphous cyclodextrin in
`water at a temperature of from about 40 to about 80° C. and
`maintaining said temperature for a period of from about 6 to
`about 24 hours;
`(ii) cooling the resultant aqueous solution to room tem(cid:173)
`perature;
`(iii) lyophilizing the cooled solution to afford an amor(cid:173)
`phous product; and
`(iv) formulating the amorphous product into a solid oral
`dosage form.
`
`BRIEF DESCRIPTION OF THE DRAWING
`
`SUMMARY OF THE INVENTION
`
`It 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 com(cid:173)
`plex, and the solid oral dosage form containing it improves
`oral bioavailability and/or achieves lower interpatient and/or
`intrapatient variation of the drug.
`The present invention provides a complex cladribine-cy(cid:173)
`clodextrin complex which is an intimate amorphous admix(cid:173)
`ture of ( a) an amorphous inclusion complex of cladribine with
`an amorphous cyclodextrin and (b) amorphous free cladrib- 30
`ine associated with amorphous cyclodextrin as a non-inclu(cid:173)
`sion 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 35
`with cladribine) and the free cladribine which forms the non(cid:173)
`inclusion complex is amorphous.
`The invention also provides a method for increasing or
`enhancing the oral bioavailability of cladribine comprising 40
`orally administering to a subject in need thereof, a pharma(cid:173)
`ceutical composition comprising a complex cladribine-cyclo(cid:173)
`dextrin complex which is an intimate amorphous admixture
`of (a) an amorphous inclusion complex of cladribine with an
`amorphous cyclodextrin and (b) amorphous free cladribine 45
`associated with amorphous cyclodextrin as a non-inclusion
`complex, formulated into a solid oral dosage form which
`maximizes the amount of cladribine in the inclusion and
`non-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 com(cid:173)
`positions of the invention for administration to treat cladrib(cid:173)
`ine-responsive conditions and for enhancing the oral bio(cid:173)
`availability of cladribine is also provided.
`Still further, the invention provides a process for the prepa(cid:173)
`ration of a complex cladribine-cyclodextrin complex which
`comprises the steps of:
`(i) combining cladribine and an amorphous cyclodextrin in
`water at a temperature of from about 40 to about 80° C. and
`maintaining said temperature for a period of from about 6 to
`about 24 hours;
`(ii) cooling the resultant aqueous solution to room tem(cid:173)
`perature; and
`(iii) lyophilizing the cooled solution to afford an amor(cid:173)
`phous product.
`
`A more complete appreciation of the invention and its
`many attendant advantages will be readily understood by
`reference to the following detailed description and the accom-
`20 parrying drawing, wherein the sole FIGURE is a graphical
`representation of the results of a phase solubility study where
`various molar concentrations ofhydroxypropyl-~-cyclodex(cid:173)
`trin (HP~CD) are plotted against various cladribine molar
`concentrations, with (e) representing the data points
`25 obtained for complexation under conditions specified in
`EXAMPLE 2 below.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Throughout the instant specification and claims, the fol(cid:173)
`lowing definitions and general statements are applicable.
`The patents, published applications, and scientific litera-
`ture referred to herein establish the knowledge of those with
`skill in the art and are hereby incorporated by reference in
`their entirety to the same extent as if each was specifically and
`individually indicated to be incorporated by reference. Any
`conflict between any reference cited herein and the specific
`teachings of this specification shall be resolved in favor of the
`latter. Likewise, any conflict between an art-understood defi(cid:173)
`nition of a word or phrase and a definition of the word or
`phrase as specifically taught in 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 of the cladribine molecule (the nitro(cid:173)
`gen-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
`50 which is not an inclusion complex; rather than the hydropho(cid:173)
`bic 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 com-
`55 plex) to the hydroxyls on the exteriorofthe cyclodextrin torus
`(e.g. in the case of hydroxypropyl-~-cyclodextrin, hydrox(cid:173)
`ypropyl and hydroxyl groups on the glucose rings). This is a
`more loosely-held association than an inclusion complex.
`As used herein, whether in a transitional phrase or in the
`60 body of a claim, the terms "comprise(s)" and "comprising"
`are to be interpreted as having an open-ended meaning. That
`is, the terms are to be 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
`65 process includes at least the recited steps, but may include
`additional steps. When used in the context of a composition,
`the term "comprising" means that the composition includes at
`
`
`
`US 8,785,415 B2
`
`5
`least the recited features or components, but may also include
`additional features or components.
`The terms "consists essentially of' or "consisting essen(cid:173)
`tially 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 composition is limited to the specified steps or 10
`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(cid:173)
`cyclodextrin complex which is an intimate, amorphous
`admixture of (a) an amorphous inclusion complex of cladrib(cid:173)
`ine with an amorphous cyclodextrin and (b) amorphous free
`cladribine associated with amorphous cyclodextrin as a non(cid:173)
`inclusion complex, formulated into a solid oral dosage form,
`so as to provide improved bioavailability and/or lower inter(cid:173)
`patient and/or intrapatient variation following administration.
`Essential to the invention is the combination of the amor(cid:173)
`phous nature 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 hydro(cid:173)
`gen bonding, which can be taken advantage of under particu(cid:173)
`lar conditions described hereinafter, and which afford a spe(cid:173)
`cial amorphous mixture uniquely well-suited for optimizing
`the oral bioavailability of cladribine.
`The terms "consists of' and "consists" are closed termi(cid:173)
`nology and allow only for the inclusion of the 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, unless the content clearly dictates other(cid:173)
`wise.
`The term "about" is used herein to means approximately, in
`the region of, roughly, 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 40
`"approximately" is used herein to modify a numerical value
`above and below the stated value by a variance of 20%.
`The term "amorphous" is used herein to refer to a noncrys(cid:173)
`talline solid. The cyclodextrins encompassed herein them(cid:173)
`selves are amorphous because they are each composed of a 45
`multitude of individual isomers, and their complexes with
`cladribine are also amorphous. Further, conditions for com(cid:173)
`plexation can be selected ( elevated temperature and pro(cid:173)
`longed complexation times, as described hereinafter) so that
`a supersaturated cladribine solution will be formed. When
`cooled, because of the amorphous nature of the complex and
`the cyclodextrin, some excess free cladribine does not pre(cid:173)
`cipitate but rather is trapped in amorphous form in intimate
`admixture, with the (preferably saturated) amorphous
`cladribine-cyclodextrin inclusion complex. This excess 55
`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 because it is in intimate admixture with the amor- 60
`phous inclusion complex, is expected to be somewhat pro(cid:173)
`tected from degradation by stomach acid ( although it may not
`be as protected as the cladribine which is in the form of the
`inclusion complex).
`The term "saturated" when used in conjunction with a 65
`complex of cladribine in amorphous cyclodextrin means that
`the complex is saturated with cladribine, that is, the complex
`
`6
`contains the maximum amount of cladribine which can be
`complexed (by means of 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 provide this information, as described in more
`detail hereinafter. (Conditions for the complexation are also
`described in more detail below.) Alternatively, a saturated
`complex may be arrived at empirically by simply adding
`cladribine to an aqueous solution of the selected cyclodextrin
`until no more cladribine goes into solution; ultimately, excess
`cladribine, if any, is removed (by filtration or centrifugation)
`and the solution lyophilized to provide the dry saturated com(cid:173)
`plex.
`The expression "substantially", as in "substantially free"
`15 means within 20% of the exact calculated amount, preferably
`within 10%, most preferably within 5%.
`The term "interpatient variability" refers to variation
`among patients to which a drug is administered. The term
`"intrapatient variability" refers to variation experienced by a
`20 single patient when dosed at different times.
`As used herein, the recitation of a 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,
`25 the variable can be equal to any integer value of the numerical
`range, including the end-points of the 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
`30 described as having values betwe