e
`US 8,785,415 B2
`(10) Patent No.:
`a2) United States Patent
`Bodoretal.
`(45) Date of Patent:
`*Jul. 22, 2014
`
`
`US008785415B2
`
`(54) ORAL FORMULATIONS OF CLADRIBINE
`
`FOREIGN PATENT DOCUMENTS
`
`(75)
`
`Inventors: Nicholas S. Bodor, Bal Harbour, FL
`(US); Yogesh Dandiker, Toronto (CA)
`F
`3
`(73) Assignee: Ares Trading S.A., Aubonne (CH)
`
`(*) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`US: Ieatey byesT days,
`This patent is subject to a terminal dis-
`claimer.
`
`be
`EP
`EP
`EP
`GB
`WO
`wo
`wo
`WO
`
`33 b oat ‘i
`iloes
`0094157 Al
`11/1983
`0 149 197 Bl
`7/1985
`0197571 A2
`10/1986
`2 189 245 A
`10/1987
`WO 90/12035 Al
`10/1990
`WOseaerag ‘I * Do0g Heese AO1K 47/48
`Wo 99/4211
`8/1999
`99/62958 Al
`12/1999
`7
`7
`OVHER PUBLICATIONS
`Redenti et al., Int. J. Pharm., 1996, 129, p. 289-294.
`Pitha et al., Life Sci., 1998, 43,
`p. 493-502.*
`fae
`Drugsin Japan (Nihon Iyakuhinn Shu), 2004 edition, Jihou Inc. Mar.
`1, 2003, pp. 651-654, “Cladrivine” (especially, “Composition”)—
`relevance explained in Jan. 10, 2012, Japanese Official Action.
`Official Action issued on Jan. 10, 2012, in corresponding Japanese
`Patent Application No. 2006-50937 1, and an English language trans-
`lation of the Official Action.
`Tarasiuk etal., “Stability of 2-Chloro-2'-Deoxyadenosine at Various
`pH and Temperature”, Archivum Immunologiae et Therapiae
`Experimentalis, vol. 42, pp. 13-15, 1994, published. by Birkhauser
`Publishers Ltd., Basel, Switzerland.
`Romineet al., “A Double-Blind, Placebo-Controlled, Randomized
`Trial of Cladribine in Relapsing-Remitting Multiple Sclerosis”, Pro-
`ceedings ofthe Association ofAmerican Physicians, vol. 111, No. 1,
`pp. 35-44, 1999, published by Blackwell Publishing, Malden, MA.
`Tortorella et al., Current Opinion on Investigational Drugs, 2(12), pp.
`1751-1756, 2001, published by PharmaPress Ltd., London, GB.
`Selby et al., “Safety and Tolerability of Subcutaneous Cladribine
`Therapyin Progressive Multiple Sclerosis”, Can. J. Neurol Sci., vol.
`25, pp. 295-299, 1998, publishedbyCanadian Journal ofNeurologi-
`cal Science, Calgary, Canada.
`Riceet al., “Cladribine and progressive MS Clinical and MRI out-
`comes of a multicenter controlled trial”, Neurology, vol. 54, pp.
`1145-1155, 2000, published by Lippincott Williams and Wilkins,
`Hagerstown, MD.
`Liliemark et al., “On the Bioavailability of Oral and Subcutaneous
`2-Chloro-2'-Deoxyadenosine in Humans: Alternative Routes of
`Administration”, Journal of Clinical Oncology, vol. 10, No. 10, pp.
`1514-1518, 1992, publishedbyAmerican Society ofClinicial Oncol-
`ogy, Alexandria, VA.
`Karlsson et al., “Oral cladribine for B-cell chronic lymphocytic
`leukaemia: report of a phaseII trial with a 3-d, 3-weekly schedule in
`untreated and pretreated patients, and a long-term follow-up of 126
`previously untreated patients”, British Journal ofHaematology, vol.
`116, pp. 538-548, 2002, published by Blackwell Science Ltd.,
`Oxford, UK.
`‘
`(Continued)
`
`Primary Examiner — Shaojia Anna Jiang
`Assistant Examiner — Jonathan S Lau
`(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.
`
`Merck 2029
`79 Claims, 1 Drawing Sheet Merck 2029
`Hopewell v Merck
`Hopewell v Merck
`IPR2023-00480
`IPR2023-00480
`
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`
`mocub
`(
`01)
`
`21)
`(21)
`22)
`(22)
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`
`(51)
`
`(56)
`
`Appl. No.: 12/986,310
`Appl.
`No
`;
`.
`Filed:
`Jan. 7, 2011
`ae
`aes
`.
`on
`Eto Rublicatiin.Data
`US 2011/0097306 Al
`Apr. 28, 2011
`Bccgd
`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 88g 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.
`~_
`;
`Int. Cl.
`anyai
`(52) U.S. Cl.
`USPC coe ceceeeeecenteeeeteeceaceneeeeees 514/46; 514/58
`(58) Field of Classification Search
`CPC wee AG1K 31/7076, A61K 47/40; A61K
`47/48969
`SPC.
`cessveswsvennmesssewevoosweumvooruccnoesendwaveennes 514/46, 58
`ee
`:
`°
`See application filefor completesearch history,
`:
`References Cited
`U.S. PATENT DOCUMENTS
`~
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`3.459.731 A
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`
`

`

`US 8,785,415 B2
` Page 2
`
`56
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`et
`al.,
`“On
`the
`bioavailability of 2-chloro-2'-
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`Ahnetal., “Chiral Recognition in Gas-Phase Cyclodextrin: Amino
`Acid Complexes—Isthe Three Point Interaction Still Valid in the Gas
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`vol. 11, pp. 1478-1481, 1997, John Wiley and Sons Ltd, England.
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`vol. 93, pp. 1716-1720, 1996, National Academy of Sciences, US.
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`Sons, Ltd., England.
`Choi et al., “FT-Raman and FT-IR Spectra of the Non-steroidal
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`Japan Society for Analytical Chemistry, Japan.
`Giordanoetal., “Thermal analysis of cyclodextrins and their inclu-
`sion compounds”, Thermochimica Acta 380, pp. 123-151, 2001,
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`Lamcharfi et al., “Electrospray Ionization Mass Spectrometry in
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`Sciences, vol. 85, No. 10, pp. 1017-1025, 1996, American Pharma-
`ceutical Association and the American Chemical Society, US.
`Meieret al., “The Influence of B- and y-Cyclodextrin Cavity Size on
`the Association Constant with Decanoate and Octanoate Anions”,
`Journal ofInclusion Phenomena and Macrocyclic Chemistry, vol.
`40, pp. 291-295, 2001, Kluwer Academic Publishers, The Nether-
`lands.
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`Mura et al., “Interactions of ketoprofen and ibuprofen with
`6-cyclodextrins in solution and in the solid state”, Znternational
`Journal of Pharmaceutics, vol. 166, pp. 189-203, 1998, Elsevier
`Science B.V., The Netherlands.
`Nolan et al., “Preparation of Vesicles and Nanoparticles of
`Amphiphilic Cyclodextrins Containing Labile Disulfide Bonds”,
`Langmuir, vol. 19, pp. 4469-4472, 2003, American Chemical Soci-
`ety, US.
`Ramanathan et al., “Electrospray Ionization Mass Spectrometric
`Study ofEncapsulation ofAmino Acids by Cyclodextrins”, J.Am Soc
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`MassSpectrometry, US.
`Redentiet al., “Raman andSolid State '3C-NMRInvestigation ofthe
`Structure of the 1 : | Amorphous Piroxicam : }-Cyclodextrin Inclu-
`sion Compound”, Biospectroscopy, vol. 5, pp. 243-251, 1999, John
`Wiley & Sons, Inc., US.
`Sipe et al., “Cladribine in treatment of chronic progressive multiple
`sclerosis”, The Lancet, vol. 344, pp. 9-13, 1994, Lancet Publishing
`Group, England.
`Szejtli, “Introduction and General Overview of Cyclodextrin Chem-
`istry”, Chem. Rev., vol. 98, pp. 1743-1753, 1998, American Chemical
`Society, US.
`Uekamaet al., “Cyclodextrin Drug Carrier Systems”, Chem. Rev,
`vol. 98, pp. 2045-2076, 1998, American Chemical Society, US.
`Uekamaet al., “Peracylated $-Cyclodextrins as Novel Sustained-
`release Carriers for a Water-soluble Drug, Molsidomine”, . Pharm.
`Pharmacol., vol. 46, pp. 714-717, 1994, Pharmaceutical Press,
`England.
`on Piroxicam
`“Influence of Environment
`al.
`et
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`Polymorphism: Vibrational Spectroscopic Study”, Biopolymers
`(Biospectroscopy), vol. 62, pp. 68-78, 2001, John Wiley & Sons,Inc.,
`US.
`Van Axel Castelli et al. “Characterisation of an Inclusion Complex
`Between Cladribine and 2-Hydroxypropyl-f-Cyclodextrin,” J
`Pharm.Sci., vol. 97, No. 9, Sep. 2008, pp. 3897-3906, Wiley
`InterScience and the American Pharmacists Association, US.
`Drugs.com, “Oral Investigational Treatment Cladribine Tablets for
`Multiple Sclerosis Significantly Reduced Relapse Rate in PhaseIII
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`com/clinical_trials/oral-investigational-cladribine-multiple-sclero-
`sis.
`
`“Serono’s Oral Cladribine for the Treatment of Multiple Sclerosis
`Awarded Fast Track Status by FDA”, accessed online Feb. 3, 2009 at
`http://prnewswire.com.
`Merck Serono NewsRelease, “Two-year Phase III Data Presented at
`AAN61st Annual Meeting Show Positive Outcome of Cladribine
`Tablets in Patients with Multiple Sclerosis”, Apr. 29/30, 2009, avail-
`able online.
`Loftsson etal., “Self-Association and Cyclodextrin Solubilization of
`Drugs”, Journal ofPharmaceutical Sciences, 2002, 91(11), p. 2307-
`2316.
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`search.eb.com/, accessed online Dec. 31, 2008.
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`Interaction Studies,’Chem. Pharm. Bull., 1988 36(2), p. 720-725.
`Suzukiet al., “A Study of 1:1 Plus 1:2 Complexes Between Barbitu-
`rate and @ -Cyclodextrin Using the Freezing Point Depression
`Method,” Chem. Pharm. Bull., 1993, 41(8), p. 1444-1447.
`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
`
`Jul. 22, 2014
`
`US 8,785,415 B2
`
`
`
`
`
`Cladribineconc.(M)
`
`0.080
`
`0.070
`
`0.060
`
`0.050
`
`0.040
`
`0.030
`
`0,020
`
`0.010
`
`0.000
`
`0.000
`
`0.050
`
`0.100
`
`0.150
`
`0.200
`
`0.250
`
`0.300
`
`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) of U.S Provi-
`sional Application No. 60/458,922, filed Mar. 28, 2003; of
`USS 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-
`porated by reference herein in their entireties and relied upon.
`
`10
`
`15
`
`BACKGROUNDOF THE INVENTION
`
`Cladribine, which is an acid-labile drug, has the chemical
`structure as set forth below:
`
`20
`
`2
`instances, therapeutic considerations such as the need fora
`slow release of cladribine over a prolonged period of time
`maybepractically met only by oral or transmucosaldelivery.
`However, to date the oral delivery of cladribine has been
`plagued by low bioavailability (see, e.g., J. Liliemarkat al., 7
`Clin. Oncol., 10(10): 1514-1518, 1992), and suboptimal
`interpatient variation (see, e.g., J. Liliemark, Clin. Pharma-
`cokinet, 32 (2): 120-131, 1997). See also, A. Tarasuik,et al.
`reporting poor absorption and pH dependentlability (Arch.
`Immunol. et Therapiae Exper., 42: 13-15, 1994).
`Cyclodextrins are cyclic oligosaccharides composed of
`cyclic a-(1—4) linked D-glucopyranoseunits. Cyclodextrins
`with six to eight units have been named a-, B- and y-cyclo-
`dextrin, respectively. The numberofunits determinesthe size
`of the cone-shaped cavity which characterizes cyclodextrins
`and into which drugs may be included to form stable com-
`plexes. A numberofderivatives of a-, B- and y-cyclodextrin
`are known in which one or more hydroxyl groups is/are
`replaced with ether groups or other radicals. These com-
`pounds are thus known complexing agents and have been
`previously used in the pharmaceuticalfield to form inclusion
`complexes with water-insoluble drugs and to thus solubilize
`them in aqueous media.
`Recently, Schultz et al., in U.S. Pat. No. 6,194,395 B1, have
`described complexing andsolubilizing cladribine with cyclo-
`dextrin. The Schultz et al. patent primarily addresses the
`problemsinherent in previously described aqueous formula-
`tions of cladribine, particularly for subcutaneous and intra-
`muscular injection. Schultz et al. have found that cladribineis
`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.
`Thelatter 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 pII of the
`stomach contents. Schultz at al. do not appear to have
`described any actual work in connection with solid oral dos-
`age forms. In fact, they describe only one methodofpreparing
`the solid dosage form, which is a melt extrusion process, in
`which the cladribine and cyclodextrin are mixed with other
`optional additives and then heated until melting occurs. Fur-
`thermore, 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 amountof cyclo-
`dextrin to be present with a given amountof cladribine in a
`solid oral dosage form. Indeed, these dosage ranges include
`many combinations which may be suitable as mixtures but
`not for complex formation. For example, a ratio of 1 mg of
`cladribine to 500 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 enough to complex that amountof cladribine.
`The Schultz et al., patent does suggest improving the sta-
`bility of cladribine in oral dosage forms by combining/com-
`Oral delivery of drugsis often preferred to parenteraldeliv-
`plexing it with cyclodextrin, but does not suggest improving
`ery for a variety of reasons, foremost patient compliance, or
`the drug’s oral bioavailability by such means; in fact, the
`for cost or therapeutic considerations. Patient compliance is
`patent does not describe or suggest a method for enhancing or
`enhanced insofar as oral dosage forms alleviate repeated
`
`health care providervisits, or the discomfort of injections or maximizing the bioavailability of cladribine fromasolid oral
`60
`prolonged infusion times associated with someactive drugs.
`dosage formof cladribine and cyclodextrin, or a composition
`At a time of escalating health care costs, the reduced costs
`specially designed to do so.
`associated with oral administration versus parenteral admin-
`Many workers have studied the solubility of specific drugs
`istration costs gain importance. The cast of parenteral admin-
`in water containing various concentrations of selected cyclo-
`istration is much higher due to the requirement that a health
`dextrins in order to demonstrate that increasing concentra-
`care professional administerthe cladribinein the health care
`tions of cyclodextrins increase the solubility of the drugsat
`providersetting, which also includesall attendant costs asso-
`selected temperatures and pH levels, as for example reported
`ciated with such administration. Furthermore,
`in certain
`in the Schultz et al. patent. Phase solubility studies have also
`
`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-
`cally in, for example, lymphomas, Langerhan’s cell histiocy-
`tosis, lupus erythematosus, chronic plaque psoriasis, Sezary
`syndrome, Bing-Neel syndrome, recurrent glioma, and solid
`tumors.
`
`OH
`
`It is also known as 2-chloro-2'-deoxyadenosine or 2-CdA.
`Cladribine exists as a white, nonhydroscopic, crystalline
`powder, consisting of individual crystals and of crystalline
`aggregates.
`Cladribine is an antimetabolite which has use in thetreat-
`
`25
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`30
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`35
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`40
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`45
`
`50
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`

`US 8,785,415 B2
`
`3
`been performedby 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, Haradaet al. U.S. Pat. No. 4,497,803, relat-
`ing to inclusion complexes of lankacidin-group antibiotics
`with cyclodextrin, and Shinodaet al. U.S. Pat. No. 4,478,995,
`relating to a complex of an acid addition salt of (2'-benzy-
`loxycarbonyl)phenyl
`trans-4-guanidinomethylcyclohexan-
`ecarboxylate with a cyclodextrin.
`While Schultz et al. teach that a cladribine-cyclodextrin
`complex improves the water solubility and acid stability of
`cladribine, the art does not suggest how to maximize or
`enhancethe benefits ofthe complexation in termsofbioavail-
`ability and interpatient variation when the complex is to be
`administered in a solid oral dosage form.
`
`SUMMARYOF THE INVENTION
`
`It has now been found that amorphous cyclodextrins can be
`combinedwith 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-
`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-
`clodextrin complex which is an intimate amorphous admix-
`ture of (a) an amorphousinclusion complex ofcladribine with
`an amorphouscyclodextrin and (b) amorphousfree cladrib-
`ine associated with amorphous cyclodextrin as a non-inclu-
`sion complex, and a pharmaceutical composition comprising
`said complex, formulatedinto 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 formsthe non-
`inclusion complex is amorphous.
`The invention also provides a method for increasing or
`enhancing the oral bioavailability of cladribine comprising
`orally administering to a subject in need thereof, a pharma-
`ceutical composition comprising a complex cladribine-cyclo-
`dextrin complex which is an 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 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-
`positions of the invention for administration to treat cladrib-
`ine-responsive conditions and for enhancing the oral bio-
`availability of cladribine is also provided.
`Still further, the invention provides a process forthe prepa-
`ration of a complex cladribine-cyclodextrin complex which
`comprises the steps of:
`(i) combining cladribine and an amorphouscyclodextrin in
`water at a temperature of from about 40 to about 80° C. and
`maintaining said temperature for a period of from about6 to
`about 24 hours;
`(i) cooling the resultant aqueous solution to room tem-
`perature; and
`(iii) lyophilizing the cooled solution to afford an amor-
`phousproduct.
`
`25
`
`30
`
`40
`
`45
`
`65
`
`4
`In yet a further aspect the invention provides a pharmaceu-
`tical composition obtainable by a process comprising the
`stepsof:
`(1) combining cladribine and an amorphouscyclodextrin in
`water at a temperature of from about 40 to about 80° C. and
`maintaining said temperature for a period of from about6 to
`about 24 hours;
`(11) cooling the resultant aqueous solution to room tem-
`perature;
`(iii) lyophilizing the cooled solution to afford an amor-
`phousproduct; and
`(iv) formulating the amorphousproduct into a solid oral
`dosage form.
`
`BRIEF DESCRIPTION OF THE DRAWING
`
`A more complete appreciation of the invention and its
`many attendant advantages will be readily understood by
`referenceto the following detailed description and the accom-
`panying drawing, wherein the sole FIGUREis a graphical
`representation ofthe results of a phase solubility study where
`various molar concentrations of hydroxypropyl-B-cyclodex-
`trin (HPBCD) are plotted against various cladribine molar
`concentrations, with (@)
`representing the data points
`obtained for complexation under conditions specified in
`EXAMPLE2 below.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Throughout the instant specification and claims, the fol-
`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
`teachingsofthis specification shall be resolved in favor ofthe
`latter. Likewise, any conflict between an art-understooddefi-
`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 ofthe cladribine molecule (thenitro-
`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
`whichis not an inclusion complex; rather than the hydropho-
`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-
`plex) to the hydroxyls on the exterior ofthe cyclodextrin torus
`(e.g. in the case of hydroxypropyl-B-cyclodextrin, hydrox-
`ypropyl and hydroxy] groups on the glucose rings). This is a
`more loosely-held association than an inclusion complex.
`Asused herein, whether in a transitional phrase or in the
`body of a claim, the terms “comprise(s)” and “comprising”
`are to be interpreted as having an open-ended meaning. That
`is, the terms are to be interpreted synonymously with the
`phrases“havingat least” or “includingat least”. When used in
`the context ofa process, the term “comprising” meansthat the
`process includesat least the recited steps, but may include
`additional steps. When used in the context of a composition,
`the term “comprising” meansthat the composition includesat
`
`

`

`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-
`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, 1.e.,
`the process or compositionis limited to the specified steps or
`materials and those which do not materially affect the basic
`and novelcharacteristics ofthe invention. The basic and novel
`
`features herein are the provision of a complex cladribine-
`cyclodextrin complex which is an intimate, amorphous
`admixture of (a) an amorphousinclusion complexofcladrib-
`ine with an 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 lowerinter-
`patient and/orintrapatientvariation following administration.
`Essential to the invention is the combination of the amor-
`
`6
`contains the maximum amountof cladribine which can be
`complexed (by means of both inclusion and non-inclusion
`complexes) with a given amount of cyclodextrin under the
`conditions ofcomplexation 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 aqueoussolution ofthe selected cyclodextrin
`until no more cladribine goes into solution; ultimately, excess
`cladribine, if any, is removed(byfiltration or centrifugation)
`and the solution lyophilized to provide the dry saturated com-
`plex.
`The expression “substantially”, as in “substantially free”
`meanswithin 20% ofthe exact calculated amount, preferably
`within 10%, most preferably within 5%.
`The term “interpatient variability” refers to variation
`among patients to which a drug is administered. The term
`“intrapatient variability”refers to variation experienced by a
`single patient when dosedat 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,
`the variable can be equalto any integer value ofthe numerical
`range, including the end-points of the range. Similarly, fora
`variable which is inherently continuous, the variable can be
`equal to any real value of the numerical range, including the
`end-points of the range. As an example, a variable which is
`described as having values between 0 and 2, can be 0, 1 or 2
`for variables which are inherently discrete, and can be 0.0,
`0.1, 0.01, 0.001, or any other real value for variables which
`are inherently continuous.
`In the specification and claims, the singular forms include
`plural referents unless the context clearly dictates otherwise.
`As used herein, unless specifically indicated otherwise, the
`word “or”is usedin the “inclusive” sense of “and/or” and not
`the “exclusive” sense of “either/or.”
`Technical andscientific terms used herein have the mean-
`ing commonly understood by oneofskill in the art to which
`the present invention pertains, unless otherwise defined. Ref-
`erence is madeherein to various methodologies and materials
`knownto those of skill in the art. Standard reference works
`
`setting forth the general principles of pharmacology include
`Goodman and Gilman’s The Pharmacological Basis of
`Therapeutics, 10Ed., McGraw Hill Companies Inc., New
`York (2001).
`Reference is madehereinafter in detail to specific embodi-
`ments of the invention. While the invention will be described
`
`in conjunction with these specific embodiments, it will be
`understood that it is not intendedto 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 the invention as
`defined by the appendedclaims. In the following description,
`numerousspecific details are set forth in order to provided a
`thorough understanding ofthe present invention. The present
`invention may be practiced without someorall of these spe-
`cific details. In other instances, well-known process opera-
`tions have not been described in detail, in order not to unnec-
`essarily obscure the present invention.
`There is provided by the present invention compositions, as
`well as methods ofmaking and ofusing pharmaceutical com-
`positions, useful to achieve desirable pharmacokinetic prop-
`erties. Such compositions stem from the discovery that solu-
`tions of cyclodextrin and cladribine in which cladribine is in
`a high thermodynamic state, when presented to the gastric
`
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`20
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`35
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`45
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`phous nature of the starting cyclodextrin, and the level of
`water solubility exhibited by cladribine (about 5 mg/ml at
`room temperature), and consequentlyits capability for hydro-
`gen bonding, which can be taken advantage of underparticu-
`lar conditions described hereinafter, and which afford a spe-
`cial amorphous mixture uniquely well-suited for optimizing
`the oral bioavailability of cladribine.
`The terms “consists of’ and “consists” are closed termi-
`
`nology andallow only for the inclusionofthe recited steps or
`features or components.
`As used herein, the singular forms “a,” “an” and “the”
`specifically also encompassthe plural forms of the terms to
`which they refer, unless the content clearly dictates other-
`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
`“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-
`talline solid. The cyclodextrins encompassed herein them-
`selves are amorphous because they are each composed of a
`multitude of individual isomers, and their complexes with
`cladribine are also amorphous. Further, conditions for com-
`plexation can be selected (elevated temperature and pro-
`longed complexation times, as described hereinafter) so that
`a supersaturated cladribine solution will be formed. When
`cooled, because of the amorphousnature of the complex and
`the cyclodextrin, some excess free cladribine does not pre-
`cipitate but rather is trapped in amorphous form in intimate
`admixture, with the (preferably saturated) amorphous
`cladribine-cyclodextrin inclusion complex. This excess
`cladribine formsa 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 amor-
`
`phous inclusion complex, is expected to be somewhat